Rhine R. Shen, David O. Ferguson, Mathilde Renard, Katrina K. Hoyer, Unkyu Kim, Xingpei Hao, ...
Most lymphomas arise by transformation of germinal center (GC) B cells. TCL1, a proto-oncogene first recognized for its role in T-cell transformation, also induces GC B-cell malignancies when...
Walkley, Carl R., Qudsi, Rameez, Sankaran, Vijay G., Perry, Jennifer A., Gostissa, Monica, Roth, Sanford I., ...
Osteosarcoma is the most common primary malignant tumor of bone. Analysis of familial cancer syndromes and sporadic cases has strongly implicated both p53 and pRb in its pathogenesis; however, the...
Tissue-specific regulation of SIRT1 by calorie restriction (2008)
Chen, Danica, Bruno, Joanne, Easlon, Erin, Lin, Su-Ju, Cheng, Hwei-Ling, Alt, Frederick W., ...
Calorie restriction (CR) has been reported to increase SIRT1 protein levels in mice, rats, and humans, and elevated activity of SIRT1 orthologs extends life span in yeast, worms, and flies. In this...
SIRT1 controls endothelial angiogenic functions during vascular growth (2007)
Potente, Michael, Ghaeni, Laleh, Baldessari, Danila, Mostoslavsky, Raul, Rossig, Lothar, Dequiedt, Franck, ...
The nicotinamide adenine dinucleotide (NAD+)-dependent histone deacetylase Sir2 regulates life-span in various species. Mammalian homologs of Sir2 are called sirtuins (SIRT1–SIRT7). In an effort to...
SirT2 is a histone deacetylase with preference for histone H4 Lys 16 during mitosis (2006)
Vaquero, Alejandro, Scher, Michael B., Lee, Dong Hoon, Sutton, Ann, Cheng, Hwei-Ling, Alt, Frederick W., ...
The mammalian cytoplasmic protein SirT2 is a member of the Sir2 family of NAD+-dependent protein deacetylases involved in caloric restriction-dependent life span extension. We found that SirT2 and...
SirT2 is a histone deacetylase with preference for histone H4 Lys 16 during mitosis (2006)
Vaquero, Alejandro, Scher, Michael B., Lee, Dong Hoon, Sutton, Ann, Cheng, Hwei-Ling, Alt, Frederick W., ...
The mammalian cytoplasmic protein SirT2 is a member of the Sir2 family of NAD+-dependent protein deacetylases involved in caloric restriction-dependent life span extension. We found that SirT2 and...
Activating Notch1 mutations in mouse models of T-ALL (2005)
O'Neil, Jennifer Elinor, Calvo, Jennifer Ann, McKenna, Keith, Krishnamoorthy, Veena, Aster, Jon C., Bassing, Craig H., ...
Recent studies have demonstrated that most patients with T-cell acute lymphocytic leukemia (T-ALL) have activating mutations in NOTCH1. We sought to determine whether these mutations are also...
Increased frequency of aberrant V(D)J recombination products in core RAG-expressing mice (2004)
Talukder, Sadiqur R., Dudley, Darryll D., Alt, Frederick W., Takahama, Yousuke, Akamatsu, Yoshiko
RAG1 and RAG2 play a central role in V(D)J recombination, a process for antigen receptor gene assembly. The truncated ‘core’ regions of RAGs are sufficient to catalyze the recombination reaction,...
Dedeoglu, Fatma, Horwitz, Bruce, Chaudhuri, Jayanta, Alt, Frederick W., Geha, Raif S.
Activation‐induced cytidine deaminase (AID) is an inducible gene that plays an important role in class switch recombination, somatic hypermutation and gene conversion in B cells. We examined the...
Rad54 and DNA Ligase IV cooperate to maintain mammalian chromatid stability (2004)
Mills, Kevin D., Ferguson, David O., Essers, Jeroen, Eckersdorff, Mark, Kanaar, Roland, Alt, Frederick W.
Nonhomologous end joining (NHEJ) and homologous recombination (HR) represent the two major pathways of DNA double-strand break (DSB) repair in eukaryotic cells. NHEJ repairs DSBs by ligation of...
Couëdel, Chrystelle, Mills, Kevin D., Barchi, Marco, Shen, Lingbo, Olshen, Adam, Johnson, Roger D., ...
Homologous recombination (HR) and nonhomologous end-joining (NHEJ) are mechanistically distinct DNA repair pathways that contribute substantially to double-strand break (DSB) repair in mammalian...
Pivniouk, Vadim I., Snapper, Scott B., Kettner, Alexander, Alenius, Harri, Laouini, Dhafer, Falet, Hervé, ...
Wiskott–Aldrich syndrome protein (WASP) is the product of the gene deficient in boys with X‐linked Wiskott–Aldrich syndrome. We assessed the role of WASP in signaling through the...
Essential role for Vav1 in activation, but not development, of {gamma}{delta} T cells (2003)
Swat, Wojciech, Xavier, Ramnik, Mizoguchi, Atsushi, Mizoguchi, Emiko, Fredericks, Jessica, Fujikawa, Keiko, ...
Vav1 is a guanine nucleotide exchange factor essential in the development and function of αβ lineage T cells. Here we report that in contrast to profound effects on pre‐TCR‐ or αβ...
O'Hagan, Rónán C., Ohh, Michael, David, Gregory, De Alboran, Ignacio Moreno, Alt, Frederick W., Kaelin, William G., ...
Malynn, Barbara A., De Alboran, Ignacio Moreno, O'Hagan, Rónán C., Bronson, Roderick, Davidson, Laurie, DePinho, Ronald A., ...
Sakai, Eiko, Bottaro, Andrea, Alt, Frederick W.
The intronic IgH enhancer Eμ, which consists of the core enhancer (cEμ) flanked by 5′ and 3′ matrix attachment regions (MAR), has been implicated in the control of IgH locus recombination and...
Xu, Yang, Davidson, Laurie, Alt, Frederick W., Baltimore, David
The pre-T-cell receptor, composed of the T-cell receptor (TCR) beta chain (TCR beta), pre-T alpha (pT alpha) chain, and CD3 molecules, has been postulated to be a transducer of signals during the...
CD40 expression and function in murine B cell ontogeny (1996)
Castigli, Emanuela, Young, Faith, Carossino, Anna Maria, Alt, Frederick W., Geha, Reif S.
The CD40 antigen, a member of the nerve growth factor/tumor necrosis factor receptor family, is expressed on all mature B lymphocytes and plays a crucial role in B cell activation, T cell-...
Mizuta, Ryushin, Taccioli, Guillermo E., Alt, Frederick W., Honjo, T.
Defective expression of the Ku80 gene has been implicated as underlying the V(D)J recombination and DNA double-strand break repair defects in the xrs-6 Chinese hamster ovary cell line. We now show...
Blunt , Tracy, Taccioli, Guillermo E., Priestley, Anne, Hafezparast, Majid, McMillan, Trevor J., Liu , Jing, ...
The Chinese hamster ovaryxrsmutants are sensitive to ionizing radiation, defective in DNA double-strand break rejoining, and unable to carry out V(D)J recombination effectively. Recently, the gene...
Generation of normal lymphocytes derived from N-myc-deficient embryonic stem cells (1995)
Malynn, Barbara A., Demengeot, Jocelyne, Stewart, Valerie, Charron, Jean, Alt, Frederick W., Hardy, R. R.
Myc family proteins are thought to be transcription factors involved in regulation of cell growth and differentiation. N-myc. is expressed at the pre-B cell stage of B cell differentiation and is...
Demengeot, Jocelyne, Oltz, Eugene M., Alt, Frederick W., Pioegh, H.
The accessibility of a chromosomally integrated TCRβ minilocus recombination substrate in a V(D)J recombinase-inducible cell line (HDR37) depends on incorporation of transcrlptlonal enhancer...
IL-2 receptor {alpha} chain expression during early B lymphocyte differentiation (1994)
Chen, Jianzhu, Ma, Averil, Young, Faith, Alt, Frederick W.
The IL-2/IL-2 receptor (IL-2R) has been studied intensively because of its potential function in the development and regulation of the immune system. The IL-2Rα chain has been shown to be...
Shinkai, Yoichi, Alt, Frederick W.
Recent studies have shown that TCR β chain expression can effect the differentiation of CD4−CD8− double-negative (DN) thymocytes to CD4+CD8+ double-positive (DP) thymocytes. The TCR β...
Li, Suzanne C., Rothman, Paul B., Zhang, Jue, Chan, Christina, Hirsh, David, Alt, Frederick W.
Germline CH transcripts initiate from a non-coding I exon and terminate downstream of the associated CH exons. Ig heavy chain class switch recombination from the VDJ - Cμ gene to particular...
Comparison of RAG gene expression in normal and transformed precursor lymphocytes (1993)
Rathbun, Gary, Oitz, Eugene M., Alt, Frederick W., Tucker, P. W.
Analyses of mechanisms that regulate V(D)J recombination have relied heavily on the use of transformed precursor lymphocyte cell lines. We now show that such lines have highly variable and frequently...
Chen, Jianzhu, Trounstine, Mary, Alt, Frederick W., Young, Faith, Kurahara, Carole, Loring, Jeanne F., ...
B lymphocyte differentiation is characterized by an ordered series of Ig gene assembly and expression events. In the majority of normal B cells, assembly and expression of Ig heavy (H) chain genes...
Collum, Robert G., Fisher, Peter E., Datta, Milton, Mellis, Scott, Thiele, Carol, Huebner, Kay, ...
We report the isolation of a novel human POU domain encoding gene named RDC-1. The POU domain of the RDC encoded protein Is highly related to the POU domain potentially encoded by the rat brain-3...
Rothman, Paul, Lutzker, Stuart, Gorham, Beverly, Stewart, Valerie, Coffman, Robert, Alt, Frederick W.
We have characterized the structure and expression of transcripts synthesized from the murlne germline immunoglobulin γ3 heavy chain gene In certain B-llneage cells. The transcripts initiate...
VH to VHDJH rearrangement is mediated by the internal VH heptamer (1990)
Covey, Lori R., Ferrier, Pierre, Alt, Frederick W.
To elucidate the mechanism of VH to VHDJH joining (VH replacement), we have assayed a pre-B cell line for ability to perform V(D)J recomblnase-medlated rearrangement events between an unrearranged VH...
Ferrier, Pierre, Covey, Lorl R., Suh, Helkyung, Winoto, Astar, Hood, Leroy, Alt, Frederick W., ...
To elucidate mechanisms that regulate ordered and tissue-specific assembly of Ig and TCR variable region gene segments, we have introduced a recombination substrate comprised of germline TCRβ V, D,...
Logtenberg, Ton, Schutte, Mieke E. M., Inghirami, Giorgio, Berman, Jeffrey E., Insel, Richard A., ...
We have studied frequencies of VH gene utilization in a panel of monoclonal Epstein–Barr virus (EBV)-transformed B cell lines derived from human adult and fetal tissues as well as in monoclonal B...
DePinho, Ronald, Kruger, Kelly, Andrews, Nancy, Lutzker, Stuart, Baltimore, David, Alt, Frederick W.
We demonstrated that a subclone of an Abelson murine leukemia virus-transformed B-lymphoid cell line switched from mu to gamma 2b expression in vitro, by the classical recombination-deletion...
Alt, Frederick W., Baltimore, David
A chromosomal segment with a unique structure around the immunoglobulin heavy chain joining region (JH) has been molecularly cloned from an Abelson murine leukemia virus-transformed cell line....
Alt, Frederick W., Rosenberg, Naomi, Enea, Vincenzo, Siden, Edward, Baltimore, David
Lymphoid cells transformed by Abelson murine leukemia virus (A-MuLV) contain three classes of RNA transcripts from immunoglobulin mu genes. P mu-mRNAs (productive) correspond to the normal...
Sakai, Eiko, Bottaro, Andrea, Davidson, Laurie, Sleckman, Barry P., Alt, Frederick W.
The intronic Ig heavy chain (IgH) enhancer, which consists of the core enhancer flanked by 5′ and 3′ matrix attachment regions, has been implicated in control of IgH locus recombination and...
Seidl, Katherine J., Manis, John P., Bottaro, Andrea, Zhang, Jue, Davidson, Laurie, Kisselgof, Alison, ...
The Ig heavy chain (IgH) constant region (CH) genes are organized from 5′ to 3′ in the order Cμ, Cδ, Cγ3, Cγ1, Cγ2b, Cγ2a, Cɛ, and Cα. Expression of CH genes downstream of Cδ involves...
Gu, Yansong, Sekiguchi, JoAnn, Gao, Yijie, Dikkes, Pieter, Frank, Karen, Ferguson, David, ...
Mammalian nonhomologous DNA end joining employs Ku70, Ku80, DNA-dependent protein kinase catalytic subunit (DNA-PKcs), XRCC4, and DNA ligase IV (Lig4). Herein, we show that Ku70 and Ku80 deficiency...
Abnormal development of Purkinje cells and lymphocytes in Atm mutant mice
Borghesani, Paul R., Alt, Frederick W., Bottaro, Andrea, Davidson, Laurie, Aksoy, Saime, Rathbun, Gary A., ...
Motor incoordination, immune deficiencies, and an increased risk of cancer are the characteristic features of the hereditary disease ataxia–telangiectasia (A-T), which is caused by mutations in the...
Mechanisms that direct ordered assembly of T cell receptor β locus V, D, and J gene segments
Sleckman, Barry P., Bassing, Craig H., Hughes, Maureen M., Okada, Ami, D'Auteuil, Margaux, Wehrly, Tara D., ...
T cell receptor (TCR) β variable region genes are assembled in progenitor T cells from germ-line Vβ, Dβ, and Jβ segments via an ordered two-step process in which Dβ to Jβ rearrangements occur...
Ferguson, David O., Sekiguchi, JoAnn M., Chang, Sandy, Frank, Karen M., Gao, Yijie, DePinho, Ronald A., ...
We have used spectral karyotyping to assess potential roles of three different components of the nonhomologous DNA end-joining pathway in the maintenance of genomic stability in mouse embryonic...
Bruton’s tyrosine kinase regulates apoptosis and JNK/SAPK kinase activity
Kawakami, Yuko, Miura, Toru, Bissonnette, Reid, Hata, Daisuke, Khan, Wasif N., Kitamura, Toshio, ...
Mast cells derived from Bruton’s tyrosine kinase (Btk)-defective xid or btk null mice showed greater expansion in culture containing interleukin-3 (IL-3) than those from wild-type (wt) mice....
RAB22 and RAB163/mouse BRCA2: Proteins that specifically interact with the RAD51 protein
Mizuta, Ryushin, LaSalle, Janine M., Cheng, Hwei-Ling, Shinohara, Akira, Ogawa, Hideyuki, Copeland, Neal, ...
The human RAD51 protein is a homologue of the bacteria RecA and yeast RAD51 proteins that are involved in homologous recombination and DNA repair. RAD51 interacts with proteins involved in...
Gu, Yansong, Jin, Shengfang, Gao, Yijie, Weaver, David T., Alt, Frederick W.
V(D)J recombination requires both lymphoid-specific and generally expressed enzymatic activities. All three known generally expressed activities involved in V(D)J recombination are also involved in...
RAG2 is regulated differentially in B and T cells by elements 5′ of the promoter
Monroe, Robert J., Chen, Feng, Ferrini, Roger, Davidson, Laurie, Alt, Frederick W.
To study RAG2 gene regulation in vivo, we developed a blastocyst complementation method in which RAG2-deficient embryonic stem cells were transfected with genomic clones containing RAG2 and then...
Induction of Ig light chain gene rearrangement in heavy chain-deficient B cells by activated Ras
Shaw, Albert C., Swat, Wojciech, Davidson, Laurie, Alt, Frederick W.
During B cell development, rearrangement and expression of Ig heavy chain (HC) genes promote development and expansion of pre-B cells accompanied by the onset of Ig light chain (LC) variable region...
Sekiguchi, JoAnn, Ferguson, David O., Chen, Hua Tang, Yang, Eva Mary, Earle, John, Frank, Karen, ...
DNA ligase IV (Lig4) and the DNA-dependent protein kinase (DNA-PK) function in nonhomologous end joining (NHEJ). However, although Lig4 deficiency causes late embryonic lethality, deficiency in...
Cloning and Functional Characterization of the Early-Lymphocyte-Specific Pb99 Gene
Sleckman, Barry P., Khan, Wasif N., Xu, Wanping, Bassing, Craig H., Malynn, Barbara A., Copeland, Neal G., ...
The Pb99 gene is specifically expressed in pre-B cells and thymocytes and not in mature B and T cells or nonlymphoid tissues, implying that it may function in early lymphoid development. We have...
Vav Family Proteins Couple to Diverse Cell Surface Receptors
Moores, Sheri L., Selfors, Laura M., Fredericks, Jessica, Breit, Timo, Fujikawa, Keiko, Alt, Frederick W., ...
Vav proteins are guanine nucleotide exchange factors for Rho family GTPases which activate pathways leading to actin cytoskeletal rearrangements and transcriptional alterations. Vav proteins contain...
Increased ionizing radiation sensitivity and genomic instability in the absence of histone H2AX
Bassing, Craig H., Chua, Katrin F., Sekiguchi, JoAnn, Suh, Heikyung, Whitlow, Scott R., Fleming, James C., ...
In mammalian cells, DNA double-strand breaks (DSBs) cause rapid phosphorylation of the H2AX core histone variant (to form γ-H2AX) in megabase chromatin domains flanking sites of DNA damage. To...
Vav3 is regulated during the cell cycle and effects cell division
Fujikawa, Keiko, Inoue, Yoshiro, Sakai, Masaharu, Koyama, Yoshikazu, Nishi, Shinzo, Funada, Ryo, ...
Vav3 is a member of the family of guanine nucleotide exchange factors implicated in the regulation of Rho GTPases. Although the exact in vivo function of Vav3 is unknown, evidence from several...
Internal IgH class switch region deletions are position-independent and enhanced by AID expression
Dudley, Darryll D., Manis, John P., Zarrin, Ali A., Kaylor, Lianne, Tian, Ming, Alt, Frederick W.
Ig heavy chain class switch recombination (CSR) involves a recombination/deletion mechanism that exchanges the expressed CH gene with a downstream CH gene. CSR is mediated by highly repetitive switch...
Bassing, Craig H., Tillman, Robert E., Woodman, Barbara B., Canty, David, Monroe, Robert J., Sleckman, Barry P., ...
T cell receptor (TCR) δ and α variable region genes are assembled from germ-line gene segments located in a single chromosomal locus in which TCRδ segments are situated between TCRα segments. The...
Novel antibody switching defects in human patients
Manis, John P., Alt, Frederick W.
Hyper-IgM syndrome (HIGM) is a primary immunodeficiency characterized by normal to elevated serum levels of IgM and low levels or the absence of IgG, IgA, and IgE. A new study AID expression in...
WAVE2 deficiency reveals distinct roles in embryogenesis and Rac-mediated actin-based motility
Yan, Catherine, Martinez-Quiles, Narcisa, Eden, Sharon, Shibata, Tomoyuki, Takeshima, Fuminao, Shinkura, Reiko, ...
The Wiskott–Aldrich syndrome related protein WAVE2 is implicated in the regulation of actin-cytoskeletal reorganization downstream of the small Rho GTPase, Rac. We inactivated the WAVE2 gene by...
Proapoptotic BID is required for myeloid homeostasis and tumor suppression
Zinkel, Sandra S., Ong, Christy C., Ferguson, David O., Iwasaki, Hiromi, Akashi, Koichi, Bronson, Roderick T., ...
The proper expansion and contraction of hematopoietic cells requires tight regulation of cell death. BID, a “BH3-only” molecule, amplifies death receptor signals connecting the extrinsic to...
Developmental defects and p53 hyperacetylation in Sir2 homolog (SIRT1)-deficient mice
Cheng, Hwei-Ling, Mostoslavsky, Raul, Saito, Shin'ichi, Manis, John P., Gu, Yansong, Patel, Parin, ...
SIRT1 is a mammalian homolog of the Saccharomyces cerevisiae chromatin silencing factor Sir2. Dominant-negative and overexpression studies have implicated a role for SIRT1 in deacetylating the p53...
Deletion of the RAG2 C terminus leads to impaired lymphoid development in mice
Akamatsu, Yoshiko, Monroe, Robert, Dudley, Darryll D., Elkin, Sheryl K., Gärtner, Frank, Talukder, Sadiqur R., ...
The recombination-activating gene (RAG)1 and RAG2 proteins comprise the lymphocyte-specific components of the V(D)J recombinase and are required for the assembly of antigen-receptor variable-region...
N-myc can functionally replace c-myc in murine development, cellular growth, and differentiation
Malynn, Barbara A., De Alboran, Ignacio Moreno, O'Hagan, Rónán C., Bronson, Roderick, Davidson, Laurie, DePinho, Ronald A., ...
Members of the myc family of cellular oncogenes have been implicated as transcriptional regulators in pathways that govern cellular proliferation and death. In addition, N-myc and c-myc are essential...
Myc-enhanced expression of Cul1 promotes ubiquitin-dependent proteolysis and cell cycle progression
O'Hagan, Rónán C., Ohh, Michael, David, Gregory, De Alboran, Ignacio Moreno, Alt, Frederick W., Kaelin, William G., ...
The c-Myc oncoprotein plays an important role in the growth and proliferation of normal and neoplastic cells. To execute these actions, c-Myc is thought to regulate functionally diverse sets of genes...
Tian, Ming, Shinkura, Reiko, Shinkura, Nobuhiko, Alt, Frederick W.
Xeroderma pigmentosum (XP) is a human genetic disease which is caused by defects in nucleotide excision repair. Since this repair pathway is responsible for removing UV irradiation-induced damage to...
Tian, Ming, Jones, David A., Smith, Michele, Shinkura, Reiko, Alt, Frederick W.
Xeroderma pigmentosum (XP) is a human disorder which is characterized by hypersensitivity to sunlight and elevated incidence of skin cancer. The disease is caused by mutations in genes that encode...
Artemis and p53 cooperate to suppress oncogenic N-myc amplification in progenitor B cells
Rooney, Sean, Sekiguchi, JoAnn, Whitlow, Scott, Eckersdorff, Mark, Manis, John P., Lee, Charles, ...
The nonhomologous DNA end-joining (NHEJ) pathway contains six known components, including Artemis, a nuclease mutated in a subset of human severe combined immunodeficient patients. Mice doubly...
Rad54 and DNA Ligase IV cooperate to maintain mammalian chromatid stability
Mills, Kevin D., Ferguson, David O., Essers, Jeroen, Eckersdorff, Mark, Kanaar, Roland, Alt, Frederick W.
Nonhomologous end joining (NHEJ) and homologous recombination (HR) represent the two major pathways of DNA double-strand break (DSB) repair in eukaryotic cells. NHEJ repairs DSBs by ligation of...
Couëdel, Chrystelle, Mills, Kevin D., Marco, Barchi, Shen, Lingbo, Olshen, Adam, Johnson, Roger D., ...
Homologous recombination (HR) and nonhomologous end-joining (NHEJ) are mechanistically distinct DNA repair pathways that contribute substantially to double-strand break (DSB) repair in mammalian...
Increased frequency of aberrant V(D)J recombination products in core RAG-expressing mice
Talukder, Sadiqur R., Dudley, Darryll D., Alt, Frederick W., Takahama, Yousuke, Akamatsu, Yoshiko
RAG1 and RAG2 play a central role in V(D)J recombination, a process for antigen receptor gene assembly. The truncated ‘core’ regions of RAGs are sufficient to catalyze the recombination reaction,...
Kang, Jian, Ferguson, David, Song, Hoseok, Bassing, Craig, Eckersdorff, Mark, Alt, Frederick W., ...
Ataxia-telangiectasia (A-T) mutated (ATM) kinase signals all three cell cycle checkpoints after DNA double-stranded break (DSB) damage. H2AX, NBS1, and p53 are substrates of ATM kinase and are...
Influence of switch region length on immunoglobulin class switch recombination
Zarrin, Ali A., Tian, Ming, Wang, Jing, Borjeson, Tiffany, Alt, Frederick W.
The class and effector functions of antibodies are modulated through the process of Ig heavy chain class switch recombination (CSR). CSR occurs between switch (S) regions that lie upstream of the...
Rooney, Sean, Alt, Frederick W., Sekiguchi, JoAnn, Manis, John P.
Assembly of Ig genes in B lineage cells involves two distinct DNA rearrangements. In early B cell development, site-specific double strand breaks (DSBs) at germ-line V, D, and J gene segments are...
Elucidation of IgH intronic enhancer functions via germ-line deletion
Perlot, Thomas, Alt, Frederick W., Bassing, Craig H., Suh, Heikyung, Pinaud, Eric
Studies of chimeric mice demonstrated that the core Ig heavy chain (IgH) intronic enhancer (iEμ) functions in V(D)J and class switch recombination at the IgH locus. To more fully evaluate the role...
53BP1 and p53 synergize to suppress genomic instability and lymphomagenesis
Morales, Julio C., Franco, Sonia, Murphy, Michael M., Bassing, Craig H., Mills, Kevin D., Adams, Melissa M., ...
p53-binding protein 1 (53BP1) participates in the cellular response to DNA double-stranded breaks where it associates with various DNA repair/cell cycle factors including the H2AX histone variant....
Early Embryonic Lethality Due to Targeted Inactivation of DNA Ligase III†
Puebla-Osorio, Nahum, Lacey, Devin B., Alt, Frederick W., Zhu, Chengming
DNA ligases catalyze the joining of strand breaks in the phosphodiester backbone of duplex DNA and play essential roles in DNA replication, recombination, repair, and maintenance of genomic...
XRCC4 suppresses medulloblastomas with recurrent translocations in p53-deficient mice
Yan, Catherine T., Kaushal, Dhruv, Murphy, Michael, Zhang, Yu, Datta, Abhishek, Chen, Changzhong, ...
Inactivation of the XRCC4 nonhomologous end-joining factor in the mouse germ line leads to embryonic lethality, in association with apoptosis of newly generated, postmitotic neurons. We now show that...
SirT2 is a histone deacetylase with preference for histone H4 Lys 16 during mitosis
Vaquero, Alejandro, Scher, Michael B., Lee, Dong Hoon, Sutton, Ann, Cheng, Hwei-Ling, Alt, Frederick W., ...
The mammalian cytoplasmic protein SirT2 is a member of the Sir2 family of NAD+-dependent protein deacetylases involved in caloric restriction-dependent life span extension. We found that SirT2 and...
Sakai, Eiko, Bottaro, Andrea, Davidson, Laurie, Sleckman, Barry P., Alt, Frederick W.
The intronic Ig heavy chain (IgH) enhancer, which consists of the core enhancer flanked by 5′ and 3′ matrix attachment regions, has been implicated in control of IgH locus recombination and...
Seidl, Katherine J., Manis, John P., Bottaro, Andrea, Zhang, Jue, Davidson, Laurie, Kisselgof, Alison, ...
The Ig heavy chain (IgH) constant region (CH) genes are organized from 5′ to 3′ in the order Cμ, Cδ, Cγ3, Cγ1, Cγ2b, Cγ2a, Cɛ, and Cα. Expression of CH genes downstream of Cδ involves...
Gu, Yansong, Sekiguchi, JoAnn, Gao, Yijie, Dikkes, Pieter, Frank, Karen, Ferguson, David, ...
Mammalian nonhomologous DNA end joining employs Ku70, Ku80, DNA-dependent protein kinase catalytic subunit (DNA-PKcs), XRCC4, and DNA ligase IV (Lig4). Herein, we show that Ku70 and Ku80 deficiency...
Abnormal development of Purkinje cells and lymphocytes in Atm mutant mice
Borghesani, Paul R., Alt, Frederick W., Bottaro, Andrea, Davidson, Laurie, Aksoy, Saime, Rathbun, Gary A., ...
Motor incoordination, immune deficiencies, and an increased risk of cancer are the characteristic features of the hereditary disease ataxia–telangiectasia (A-T), which is caused by mutations in the...
Mechanisms that direct ordered assembly of T cell receptor β locus V, D, and J gene segments
Sleckman, Barry P., Bassing, Craig H., Hughes, Maureen M., Okada, Ami, D'Auteuil, Margaux, Wehrly, Tara D., ...
T cell receptor (TCR) β variable region genes are assembled in progenitor T cells from germ-line Vβ, Dβ, and Jβ segments via an ordered two-step process in which Dβ to Jβ rearrangements occur...
Ferguson, David O., Sekiguchi, JoAnn M., Chang, Sandy, Frank, Karen M., Gao, Yijie, DePinho, Ronald A., ...
We have used spectral karyotyping to assess potential roles of three different components of the nonhomologous DNA end-joining pathway in the maintenance of genomic stability in mouse embryonic...
Bruton’s tyrosine kinase regulates apoptosis and JNK/SAPK kinase activity
Kawakami, Yuko, Miura, Toru, Bissonnette, Reid, Hata, Daisuke, Khan, Wasif N., Kitamura, Toshio, ...
Mast cells derived from Bruton’s tyrosine kinase (Btk)-defective xid or btk null mice showed greater expansion in culture containing interleukin-3 (IL-3) than those from wild-type (wt) mice....
RAB22 and RAB163/mouse BRCA2: Proteins that specifically interact with the RAD51 protein
Mizuta, Ryushin, LaSalle, Janine M., Cheng, Hwei-Ling, Shinohara, Akira, Ogawa, Hideyuki, Copeland, Neal, ...
The human RAD51 protein is a homologue of the bacteria RecA and yeast RAD51 proteins that are involved in homologous recombination and DNA repair. RAD51 interacts with proteins involved in...
Gu, Yansong, Jin, Shengfang, Gao, Yijie, Weaver, David T., Alt, Frederick W.
V(D)J recombination requires both lymphoid-specific and generally expressed enzymatic activities. All three known generally expressed activities involved in V(D)J recombination are also involved in...
RAG2 is regulated differentially in B and T cells by elements 5′ of the promoter
Monroe, Robert J., Chen, Feng, Ferrini, Roger, Davidson, Laurie, Alt, Frederick W.
To study RAG2 gene regulation in vivo, we developed a blastocyst complementation method in which RAG2-deficient embryonic stem cells were transfected with genomic clones containing RAG2 and then...
Induction of Ig light chain gene rearrangement in heavy chain-deficient B cells by activated Ras
Shaw, Albert C., Swat, Wojciech, Davidson, Laurie, Alt, Frederick W.
During B cell development, rearrangement and expression of Ig heavy chain (HC) genes promote development and expansion of pre-B cells accompanied by the onset of Ig light chain (LC) variable region...
Sekiguchi, JoAnn, Ferguson, David O., Chen, Hua Tang, Yang, Eva Mary, Earle, John, Frank, Karen, ...
DNA ligase IV (Lig4) and the DNA-dependent protein kinase (DNA-PK) function in nonhomologous end joining (NHEJ). However, although Lig4 deficiency causes late embryonic lethality, deficiency in...
Cloning and Functional Characterization of the Early-Lymphocyte-Specific Pb99 Gene
Sleckman, Barry P., Khan, Wasif N., Xu, Wanping, Bassing, Craig H., Malynn, Barbara A., Copeland, Neal G., ...
The Pb99 gene is specifically expressed in pre-B cells and thymocytes and not in mature B and T cells or nonlymphoid tissues, implying that it may function in early lymphoid development. We have...
Vav Family Proteins Couple to Diverse Cell Surface Receptors
Moores, Sheri L., Selfors, Laura M., Fredericks, Jessica, Breit, Timo, Fujikawa, Keiko, Alt, Frederick W., ...
Vav proteins are guanine nucleotide exchange factors for Rho family GTPases which activate pathways leading to actin cytoskeletal rearrangements and transcriptional alterations. Vav proteins contain...
Increased ionizing radiation sensitivity and genomic instability in the absence of histone H2AX
Bassing, Craig H., Chua, Katrin F., Sekiguchi, JoAnn, Suh, Heikyung, Whitlow, Scott R., Fleming, James C., ...
In mammalian cells, DNA double-strand breaks (DSBs) cause rapid phosphorylation of the H2AX core histone variant (to form γ-H2AX) in megabase chromatin domains flanking sites of DNA damage. To...
Vav3 is regulated during the cell cycle and effects cell division
Fujikawa, Keiko, Inoue, Yoshiro, Sakai, Masaharu, Koyama, Yoshikazu, Nishi, Shinzo, Funada, Ryo, ...
Vav3 is a member of the family of guanine nucleotide exchange factors implicated in the regulation of Rho GTPases. Although the exact in vivo function of Vav3 is unknown, evidence from several...
Internal IgH class switch region deletions are position-independent and enhanced by AID expression
Dudley, Darryll D., Manis, John P., Zarrin, Ali A., Kaylor, Lianne, Tian, Ming, Alt, Frederick W.
Ig heavy chain class switch recombination (CSR) involves a recombination/deletion mechanism that exchanges the expressed CH gene with a downstream CH gene. CSR is mediated by highly repetitive switch...
Bassing, Craig H., Tillman, Robert E., Woodman, Barbara B., Canty, David, Monroe, Robert J., Sleckman, Barry P., ...
T cell receptor (TCR) δ and α variable region genes are assembled from germ-line gene segments located in a single chromosomal locus in which TCRδ segments are situated between TCRα segments. The...
Novel antibody switching defects in human patients
Manis, John P., Alt, Frederick W.
Hyper-IgM syndrome (HIGM) is a primary immunodeficiency characterized by normal to elevated serum levels of IgM and low levels or the absence of IgG, IgA, and IgE. A new study AID expression in...
WAVE2 deficiency reveals distinct roles in embryogenesis and Rac-mediated actin-based motility
Yan, Catherine, Martinez-Quiles, Narcisa, Eden, Sharon, Shibata, Tomoyuki, Takeshima, Fuminao, Shinkura, Reiko, ...
The Wiskott–Aldrich syndrome related protein WAVE2 is implicated in the regulation of actin-cytoskeletal reorganization downstream of the small Rho GTPase, Rac. We inactivated the WAVE2 gene by...
Proapoptotic BID is required for myeloid homeostasis and tumor suppression
Zinkel, Sandra S., Ong, Christy C., Ferguson, David O., Iwasaki, Hiromi, Akashi, Koichi, Bronson, Roderick T., ...
The proper expansion and contraction of hematopoietic cells requires tight regulation of cell death. BID, a “BH3-only” molecule, amplifies death receptor signals connecting the extrinsic to...
Developmental defects and p53 hyperacetylation in Sir2 homolog (SIRT1)-deficient mice
Cheng, Hwei-Ling, Mostoslavsky, Raul, Saito, Shin'ichi, Manis, John P., Gu, Yansong, Patel, Parin, ...
SIRT1 is a mammalian homolog of the Saccharomyces cerevisiae chromatin silencing factor Sir2. Dominant-negative and overexpression studies have implicated a role for SIRT1 in deacetylating the p53...
Deletion of the RAG2 C terminus leads to impaired lymphoid development in mice
Akamatsu, Yoshiko, Monroe, Robert, Dudley, Darryll D., Elkin, Sheryl K., Gärtner, Frank, Talukder, Sadiqur R., ...
The recombination-activating gene (RAG)1 and RAG2 proteins comprise the lymphocyte-specific components of the V(D)J recombinase and are required for the assembly of antigen-receptor variable-region...
N-myc can functionally replace c-myc in murine development, cellular growth, and differentiation
Malynn, Barbara A., De Alboran, Ignacio Moreno, O'Hagan, Rónán C., Bronson, Roderick, Davidson, Laurie, DePinho, Ronald A., ...
Members of the myc family of cellular oncogenes have been implicated as transcriptional regulators in pathways that govern cellular proliferation and death. In addition, N-myc and c-myc are essential...
Myc-enhanced expression of Cul1 promotes ubiquitin-dependent proteolysis and cell cycle progression
O'Hagan, Rónán C., Ohh, Michael, David, Gregory, De Alboran, Ignacio Moreno, Alt, Frederick W., Kaelin, William G., ...
The c-Myc oncoprotein plays an important role in the growth and proliferation of normal and neoplastic cells. To execute these actions, c-Myc is thought to regulate functionally diverse sets of genes...
Tian, Ming, Shinkura, Reiko, Shinkura, Nobuhiko, Alt, Frederick W.
Xeroderma pigmentosum (XP) is a human genetic disease which is caused by defects in nucleotide excision repair. Since this repair pathway is responsible for removing UV irradiation-induced damage to...
Tian, Ming, Jones, David A., Smith, Michele, Shinkura, Reiko, Alt, Frederick W.
Xeroderma pigmentosum (XP) is a human disorder which is characterized by hypersensitivity to sunlight and elevated incidence of skin cancer. The disease is caused by mutations in genes that encode...
Artemis and p53 cooperate to suppress oncogenic N-myc amplification in progenitor B cells
Rooney, Sean, Sekiguchi, JoAnn, Whitlow, Scott, Eckersdorff, Mark, Manis, John P., Lee, Charles, ...
The nonhomologous DNA end-joining (NHEJ) pathway contains six known components, including Artemis, a nuclease mutated in a subset of human severe combined immunodeficient patients. Mice doubly...
Rad54 and DNA Ligase IV cooperate to maintain mammalian chromatid stability
Mills, Kevin D., Ferguson, David O., Essers, Jeroen, Eckersdorff, Mark, Kanaar, Roland, Alt, Frederick W.
Nonhomologous end joining (NHEJ) and homologous recombination (HR) represent the two major pathways of DNA double-strand break (DSB) repair in eukaryotic cells. NHEJ repairs DSBs by ligation of...
Couëdel, Chrystelle, Mills, Kevin D., Marco, Barchi, Shen, Lingbo, Olshen, Adam, Johnson, Roger D., ...
Homologous recombination (HR) and nonhomologous end-joining (NHEJ) are mechanistically distinct DNA repair pathways that contribute substantially to double-strand break (DSB) repair in mammalian...
Increased frequency of aberrant V(D)J recombination products in core RAG-expressing mice
Talukder, Sadiqur R., Dudley, Darryll D., Alt, Frederick W., Takahama, Yousuke, Akamatsu, Yoshiko
RAG1 and RAG2 play a central role in V(D)J recombination, a process for antigen receptor gene assembly. The truncated ‘core’ regions of RAGs are sufficient to catalyze the recombination reaction,...
Kang, Jian, Ferguson, David, Song, Hoseok, Bassing, Craig, Eckersdorff, Mark, Alt, Frederick W., ...
Ataxia-telangiectasia (A-T) mutated (ATM) kinase signals all three cell cycle checkpoints after DNA double-stranded break (DSB) damage. H2AX, NBS1, and p53 are substrates of ATM kinase and are...
Influence of switch region length on immunoglobulin class switch recombination
Zarrin, Ali A., Tian, Ming, Wang, Jing, Borjeson, Tiffany, Alt, Frederick W.
The class and effector functions of antibodies are modulated through the process of Ig heavy chain class switch recombination (CSR). CSR occurs between switch (S) regions that lie upstream of the...
Rooney, Sean, Alt, Frederick W., Sekiguchi, JoAnn, Manis, John P.
Assembly of Ig genes in B lineage cells involves two distinct DNA rearrangements. In early B cell development, site-specific double strand breaks (DSBs) at germ-line V, D, and J gene segments are...
Elucidation of IgH intronic enhancer functions via germ-line deletion
Perlot, Thomas, Alt, Frederick W., Bassing, Craig H., Suh, Heikyung, Pinaud, Eric
Studies of chimeric mice demonstrated that the core Ig heavy chain (IgH) intronic enhancer (iEμ) functions in V(D)J and class switch recombination at the IgH locus. To more fully evaluate the role...
53BP1 and p53 synergize to suppress genomic instability and lymphomagenesis
Morales, Julio C., Franco, Sonia, Murphy, Michael M., Bassing, Craig H., Mills, Kevin D., Adams, Melissa M., ...
p53-binding protein 1 (53BP1) participates in the cellular response to DNA double-stranded breaks where it associates with various DNA repair/cell cycle factors including the H2AX histone variant....
XRCC4 suppresses medulloblastomas with recurrent translocations in p53-deficient mice
Yan, Catherine T., Kaushal, Dhruv, Murphy, Michael, Zhang, Yu, Datta, Abhishek, Chen, Changzhong, ...
Inactivation of the XRCC4 nonhomologous end-joining factor in the mouse germ line leads to embryonic lethality, in association with apoptosis of newly generated, postmitotic neurons. We now show that...
SirT2 is a histone deacetylase with preference for histone H4 Lys 16 during mitosis
Vaquero, Alejandro, Scher, Michael B., Lee, Dong Hoon, Sutton, Ann, Cheng, Hwei-Ling, Alt, Frederick W., ...
The mammalian cytoplasmic protein SirT2 is a member of the Sir2 family of NAD+-dependent protein deacetylases involved in caloric restriction-dependent life span extension. We found that SirT2 and...
Early Embryonic Lethality Due to Targeted Inactivation of DNA Ligase III†
Puebla-Osorio, Nahum, Lacey, Devin B., Alt, Frederick W., Zhu, Chengming
DNA ligases catalyze the joining of strand breaks in the phosphodiester backbone of duplex DNA and play essential roles in DNA replication, recombination, repair, and maintenance of genomic...
Innate immune response to encephalomyocarditis virus infection mediated by CD1d
Exley, Mark A, Bigley, Nancy J, Cheng, Olivia, Shaulov, Angela, Tahir, Syed Muhammad Ali, Carter, Quincy L, ...
CD1d-reactive natural killer T (NKT) cells can rapidly produce T helper type 1 (Th1) and/or Th2 cytokines, can activate antigen-presenting cell (APC) interleukin-12 (IL-12) production, and are...
Complete correction of murine Artemis immunodeficiency by lentiviral vector-mediated gene transfer
Mostoslavsky, Gustavo, Fabian, Attila J., Rooney, Sean, Alt, Frederick W., Mulligan, Richard C.
Artemis gene mutations are responsible for the development of a severe combined immunodeficiency [radiation-sensitive (RS) SCID] characterized by a severe B and T cell deficiency and a normal natural...
Activating Notch1 mutations in mouse models of T-ALL
O'Neil, Jennifer, Calvo, Jennifer, McKenna, Keith, Krishnamoorthy, Veena, Aster, Jon C., Bassing, Craig H., ...
Recent studies have demonstrated that most patients with T-cell acute lymphocytic leukemia (T-ALL) have activating mutations in NOTCH1. We sought to determine whether these mutations are also...
Wu, Cherry, Ranganath, Sheila, Gleason, Megan, Woodman, Barbara B., Borjeson, Tiffany M., Alt, Frederick W., ...
T cell antigen receptor (TCR)β V(D)J variable region exon assembly is ordered, with Dβ to Jβ rearrangements occurring before joining of Vβs to a DJβ complex. Germ-line V(D)J segments are flanked...
Defective DNA repair and increased genomic instability in Cernunnos-XLF-deficient murine ES cells
Zha, Shan, Alt, Frederick W., Cheng, Hwei-Ling, Brush, James W., Li, Gang
Nonhomologous DNA end-joining (NHEJ) is a major pathway of DNA double-strand break (DSB) repair in mammalian cells, and it functions to join both specifically programmed DSBs that occur in the...
Shen, Rhine R., Ferguson, David O., Renard, Mathilde, Hoyer, Katrina K., Kim, Unkyu, Hao, Xingpei, ...
Most lymphomas arise by transformation of germinal center (GC) B cells. TCL1, a proto-oncogene first recognized for its role in T-cell transformation, also induces GC B-cell malignancies when...
Aifantis, Iannis, Bassing, Craig H., Garbe, Annette I., Sawai, Katie, Alt, Frederick W., Von Boehmer, Harald
It is well established that the pre–T cell receptor for antigen (TCR) is responsible for efficient expansion and differentiation of thymocytes with productive TCRβ rearrangements. However, Ptcra-...
Wiskott–Aldrich syndrome protein (WASP) and N-WASP are critical for T cell development
Westerberg, Lisa, Maillard, Michel H., Onaldi, Dilek, Wachtel, Heather, Meelu, Parool, ...
Although T cell dysfunction and lymphopenia are key features of immunodeficient patients with the Wiskott–Aldrich syndrome and Wiskott–Aldrich syndrome protein (WASP)-deficient mice, T cell...
Mammalian Sir2 Homolog SIRT3 Regulates Global Mitochondrial Lysine Acetylation▿ †
Lombard, David B., Alt, Frederick W., Cheng, Hwei-Ling, Bunkenborg, Jakob, Streeper, Ryan S., Mostoslavsky, Raul, ...
Homologs of the Saccharomyces cerevisiae Sir2 protein, sirtuins, promote longevity in many organisms. Studies of the sirtuin SIRT3 have so far been limited to cell culture systems. Here, we...
Metabolic control of muscle mitochondrial function and fatty acid oxidation through SIRT1/PGC-1α
Gerhart-Hines, Zachary, Rodgers, Joseph T, Bare, Olivia, Lerin, Carles, Kim, Seung-Hee, Mostoslavsky, Raul, ...
In mammals, maintenance of energy and nutrient homeostasis during food deprivation is accomplished through an increase in mitochondrial fatty acid oxidation in peripheral tissues. An important...
Defective DNA Repair and Increased Genomic Instability in Artemis-deficient Murine Cells
Rooney, Sean, Alt, Frederick W., Lombard, David, Whitlow, Scott, Eckersdorff, Mark, Fleming, James, ...
In developing lymphocytes, the recombination activating gene endonuclease cleaves DNA between V, D, or J coding and recombination signal (RS) sequences to form hairpin coding and blunt RS ends, which...
Deficiencies of GM-CSF and Interferon γ Link Inflammation and Cancer
Enzler, Thomas, Gillessen, Silke, Manis, John P., Ferguson, David, Fleming, James, Alt, Frederick W., ...
Chronic inflammation contributes to carcinogenesis, but the underlying mechanisms are poorly understood. We report that aged granulocyte-macrophage colony stimulating factor (GM-CSF)-deficient mice...
Ye, Qunrui, Press, Barry, Kissler, Stephan, Yang, Xiao-Feng, Lu, Linrong, Bassing, Craig H., ...
The molecular basis of CD28-dependent costimulation of T cells is poorly understood. Bcl-xγ is a member of the Bcl-x family whose expression is restricted to activated T cells and requires...
Fujikawa, Keiko, Miletic, Ana V., Alt, Frederick W., Faccio, Roberta, Brown, Tracie, Hoog, Jeremy, ...
The Vav family of Rho guanine nucleotide exchange factors is thought to orchestrate signaling events downstream of lymphocyte antigen receptors. Elucidation of Vav function has been obscured thus far...
Impaired V(D)J Recombination and Lymphocyte Development in Core RAG1-expressing Mice
Dudley, Darryll D., Sekiguchi, JoAnn, Zhu, Chengming, Sadofsky, Moshe J., Whitlow, Scott, DeVido, Jeffrey, ...
RAG1 and RAG2 are the lymphocyte-specific components of the V(D)J recombinase. In vitro analyses of RAG function have relied on soluble, highly truncated “core” RAG proteins. To identify...
SIRT1 controls endothelial angiogenic functions during vascular growth
Potente, Michael, Ghaeni, Laleh, Baldessari, Danila, Mostoslavsky, Raul, Rossig, Lothar, Dequiedt, Franck, ...
The nicotinamide adenine dinucleotide (NAD+)-dependent histone deacetylase Sir2 regulates life-span in various species. Mammalian homologs of Sir2 are called sirtuins (SIRT1–SIRT7). In an effort to...
Shaw, Albert C., Swat, Wojciech, Ferrini, Roger, Davidson, Laurie, Alt, Frederick W.
To elucidate the intracellular pathways that mediate early B cell development, we directed expression of activated Ras to the B cell lineage in the context of the recombination-activating gene 1...
Aifantis, Iannis, Pivniouk, Vadim I., Gärtner, Frank, Feinberg, Jacqueline, Swat, Wojciech, Alt, Frederick W., ...
Signaling via the pre-T cell receptor (TCR) is required for the proliferative expansion and maturation of CD4−CD8− double-negative (DN) thymocytes into CD4+CD8+ double-positive (DP) cells and for...
Suzuki, Harumi, Shinkai, Yoichi, Granger, Lawrence G., Alt, Frederick W., Love, Paul E., Singer, Alfred
As a consequence of positive selection in the thymus, immature CD4+8+ double-positive, [DP] thymocytes selectively terminate synthesis of one coreceptor molecule and, as a result, differentiate into...
Hata, Daisuke, Kawakami, Yuko, Inagaki, Naoki, Lantz, Chris S., Kitamura, Toshio, Khan, Wasif N., ...
We investigated the role of Bruton's tyrosine kinase (Btk) in FcεRI-dependent activation of mouse mast cells, using xid and btk null mutant mice. Unlike B cell development, mast cell development is...
Ku70 Is Required for Late B Cell Development and Immunoglobulin Heavy Chain Class Switching
Manis, John P., Gu, Yansong, Lansford, Rusty, Sonoda, Eiichiro, Ferrini, Roger, Davidson, Laurie, ...
Immunoglobulin (Ig) heavy chain (HC) class switch recombination (CSR) is a late B cell process that involves intrachromosomal DNA rearrangement. Ku70 and Ku80 form a DNA end-binding complex required...
Independent and Opposing Roles For Btk and Lyn in B and Myeloid Signaling Pathways
Satterthwaite, Anne B., Lowell, Clifford A., Khan, Wasif N., Sideras, Paschalis, Alt, Frederick W., Witte, Owen N.
Transphosphorylation by Src family kinases is required for the activation of Bruton's tyrosine kinase (Btk). Differences in the phenotypes of Btk−/− and lyn−/− mice suggest that these kinases...
Class Switching in B Cells Lacking 3′ Immunoglobulin Heavy Chain Enhancers
Manis, John P., Van Der Stoep, Nienke, Tian, Ming, Ferrini, Roger, Davidson, Laurie, Bottaro, Andrea, ...
The 40-kb region downstream of the most 3′ immunoglobulin (Ig) heavy chain constant region gene (Cα) contains a series of transcriptional enhancers speculated to play a role in Ig heavy chain...
Gärtner, Frank, Alt, Frederick W., Monroe, Robert J., Seidl, Katherine J.
Splenic B lineage cells expressing recombination activation genes (RAG+) in mice immunized with 4-hydroxy-3-nitrophenyl-acetyl coupled to chicken γ-globulin (NP-CGG) and the adjuvant...
Assembly of Productive T Cell Receptor δ Variable Region Genes Exhibits Allelic Inclusion
Sleckman, Barry P., Khor, Bernard, Monroe, Robert, Alt, Frederick W.
The generation of a productive “in-frame” T cell receptor β (TCR β), immunoglobulin (Ig) heavy (H) or Ig light (L) chain variable region gene can result in the cessation of rearrangement of the...
Zhang, Yu, Kwon, SoHee, Yamaguchi, Teppei, Cubizolles, Fabien, Rousseaux, Sophie, Kneissel, Michaela, ...
Posttranslational modifications play important roles in regulating protein structure and function. Histone deacetylase 6 (HDAC6) is a mostly cytoplasmic class II HDAC, which has a unique structure...
A role for the NAD-dependent deacetylase Sirt1 in the regulation of autophagy
Lee, In Hye, Cao, Liu, Mostoslavsky, Raul, Lombard, David B., Liu, Jie, Bruns, Nicholas E., ...
We demonstrate a role for the NAD-dependent deacetylase Sirt1 in the regulation of autophagy. In particular, transient increased expression of Sirt1 is sufficient to stimulate basal rates of...
Antisense transcripts from immunoglobulin heavy-chain locus V(D)J and switch regions
Perlot, Thomas, Li, Gang, Alt, Frederick W.
Activation-induced cytosine deaminase (AID) is essential for both somatic hypermutation (SHM) and class switch recombination (CSR), two processes involved in antibody diversification. Previously,...
Franco, Sonia, Murphy, Michael M., Li, Gang, Borjeson, Tiffany, Boboila, Cristian, Alt, Frederick W.
The DNA-dependent protein kinase catalytic subunit (DNA-PKcs) and Artemis are classical nonhomologous DNA end-joining (C-NHEJ) factors required for joining a subset of DNA double-strand breaks (DSB),...
Walkley, Carl R., Qudsi, Rameez, Sankaran, Vijay G., Perry, Jennifer A., Gostissa, Monica, Roth, Sanford I., ...
Osteosarcoma is the most common primary malignant tumor of bone. Analysis of familial cancer syndromes and sporadic cases has strongly implicated both p53 and pRb in its pathogenesis; however, the...
Tissue-specific regulation of SIRT1 by calorie restriction
Chen, Danica, Bruno, Joanne, Easlon, Erin, Lin, Su-Ju, Cheng, Hwei-Ling, Alt, Frederick W., ...
Calorie restriction (CR) has been reported to increase SIRT1 protein levels in mice, rats, and humans, and elevated activity of SIRT1 orthologs extends life span in yeast, worms, and flies. In this...
Sγ3 switch sequences function in place of endogenous Sγ1 to mediate antibody class switching
Zarrin, Ali A., Goff, Peter H., Senger, Kate, Alt, Frederick W.
Immunoglobulin heavy chain (IgH) class switch recombination (CSR) replaces the initially expressed IgH Cμ exons with a set of downstream IgH constant region (CH) exons. Individual sets of CH exons...
Complementary functions of ATM and H2AX in development and suppression of genomic instability
Zha, Shan, Sekiguchi, JoAnn, Brush, James W., Bassing, Craig H., Alt, Frederick W.
Upon DNA damage, histone H2AX is phosphorylated by ataxia-telangiectasia mutated (ATM) and other phosphoinositide 3-kinase-related protein kinases. To elucidate further the potential overlapping and...
Bassing, Craig H., Ranganath, Sheila, Murphy, Mike, Savic, Velibor, Gleason, Meagan, Alt, Frederick W.
Histone H2AX is required to maintain genomic stability in cells and to suppress malignant transformation of lymphocytes in mice. H2ax−/−p53−/− mice succumb predominantly to immature αβ...
Giblin, William, Chatterji, Monalisa, Westfield, Gerwin, Masud, Tehmina, Theisen, Brian, Cheng, Hwei-Ling, ...
The RAG1/2 endonuclease initiates programmed DNA rearrangements in progenitor lymphocytes by generating double-strand breaks at specific recombination signal sequences. This process, known as V(D)J...
Wang, Jing H., Alt, Frederick W., Gostissa, Monica, Datta, Abhishek, Murphy, Michael, Alimzhanov, Marat B., ...
Nonhomologous end-joining (NHEJ) repairs DNA double-strand breaks (DSBs) during V(D)J recombination in developing lymphocytes and during immunoglobulin (Ig) heavy chain (IgH) class switch...
Schenten, Dominik, Kracker, Sven, Esposito, Gloria, Franco, Sonia, Klein, Ulf, Murphy, Michael, ...
Polζ is an error-prone DNA polymerase that is critical for embryonic development and maintenance of genome stability. To analyze its suggested role in somatic hypermutation (SHM) and possible...
Chromosomal location targets different MYC family gene members for oncogenic translocations
Gostissa, Monica, Ranganath, Sheila, Bianco, Julia M., Alt, Frederick W.
The MYC family of cellular oncogenes includes c-Myc, N-myc, and L-myc, which encode transcriptional regulators involved in the control of cell proliferation and death. Accordingly, these genes become...
Cheng, Hwei-Ling, Vuong, Bao Q., Basu, Uttiya, Franklin, Andrew, Schwer, Bjoern, Astarita, Jillian, ...
Activation-induced cytidine deaminase (AID) is a single-stranded (ss) DNA-specific cytidine deaminase that initiates Ig heavy chain (IgH) class switch recombination (CSR) and Ig somatic hypermutation...
Chakraborty, Tirtha, Perlot, Thomas, Subrahmanyam, Ramesh, Jani, Anant, Goff, Peter H., Zhang, Yu, ...
A tissue-specific transcriptional enhancer, Eμ, has been implicated in developmentally regulated recombination and transcription of the immunoglobulin heavy chain (IgH) gene locus. We demonstrate...