Photo of Frederick W. Alt,  PhD

Frederick W. Alt, PhD

Boston Children's Hospital

Boston Children's Hospital
Phone: (617) 919-2539
Fax: (617) 730-0948


Alt@enders.tch.harvard.edu

Frederick W. Alt, PhD

Boston Children's Hospital

EDUCATIONAL TITLES

  • Charles A. Janeway Professor of Pediatrics, Pediatrics, Harvard Medical School
  • Professor, Genetics, Harvard Medical School
  • Investigator, Howard Hughes Medical Institute, Boston Children's Hospital

DF/HCC PROGRAM AFFILIATION

Research Abstract

The broad focus of the Alt lab is the elucidation of mechanisms that generate antigen receptor diversity in the Immune system and mechanisms that maintain genomic stability in mammalian cells. More specifically, the lab studies V(D)J recombination in developing B and T lymphocytes and IgH heavy chain class switch recombination (CSR) and somatic hypermutation in mature B lymphocytes. Studies of these processes continue to employ biochemical, molecular and mouse modeling approaches to elucidate mechanisms by which the RAG endonuclease and Activation Induced Cytidine Deaminase function on DNA to initiate, respectively, VDJ recombination and CSR. One focus of this work is to elucidate how the DNA lesion generating activities of these lymphocyte-specific enzymes is directed to specific antigen receptor locus substrates and not to off targets that could generate chromosomal translocations and deletions that contribute to lymphoid cancers. Other studies are aimed at elucidating roles of general DNA double strand break (DSB) repair and response pathways in VDJ recombination and CSR, and the interplay of DSB repair and response pathways in suppressing genomic instability and cancer. A major new lab research area focuses on how organization of the genome in the nucleus influences programmed gene rearrangements and chromosomal translocations. For this purpose, the lab developed a high throughput genomic translocation sequencing (HTGTS) to identify the translocations genome wide that arise from fixed DSBs. This approach also identifies sites of endogenous genomic DSBs including RAG or AID off-target sequences and transcription start sites. Ongoing work seeks to elucidate mechanistic elements (three dimensional genome organization, DSBs, transcription, epigenetic modifications, repair pathways, etc) that contribute to the formation of translocations and other forms of genomic instability in mouse and human cancer cells.

Publications

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  • Lin SG, Ba Z, Du Z, Zhang Y, Hu J, Alt FW. Highly sensitive and unbiased approach for elucidating antibody repertoires. Proc Natl Acad Sci U S A 2016. PubMed
  • Hu J, Meyers RM, Dong J, Panchakshari RA, Alt FW, Frock RL. Detecting DNA double-stranded breaks in mammalian genomes by linear amplification-mediated high-throughput genome-wide translocation sequencing. Nat Protoc 2016; 11:853-71. PubMed
  • Schwer B, Wei PC, Chang AN, Kao J, Du Z, Meyers RM, Alt FW. Transcription-associated processes cause DNA double-strand breaks and translocations in neural stem/progenitor cells. Proc Natl Acad Sci U S A 2016; 113:2258-63. PubMed
  • Wei PC, Chang AN, Kao J, Du Z, Meyers RM, Alt FW, Schwer B. Long Neural Genes Harbor Recurrent DNA Break Clusters in Neural Stem/Progenitor Cells. Cell 2016; 164:644-55. PubMed
  • Garot A, Marquet M, Saintamand A, Bender S, Le Noir S, Rouaud P, Carrion C, Oruc Z, Bébin AG, Moreau J, Lebrigand K, Denizot Y, Alt FW, Cogné M, Pinaud E. Sequential activation and distinct functions for distal and proximal modules within the IgH 3' regulatory region. Proc Natl Acad Sci U S A 2016; 113:1618-23. PubMed
  • Yeap LS, Hwang JK, Du Z, Meyers RM, Meng FL, Jakubauskaitė A, Liu M, Mani V, Neuberg D, Kepler TB, Wang JH, Alt FW. Sequence-Intrinsic Mechanisms that Target AID Mutational Outcomes on Antibody Genes. Cell 2015; 163:1124-37. PubMed
  • Hu J, Zhang Y, Zhao L, Frock RL, Du Z, Meyers RM, Meng FL, Schatz DG, Alt FW. Chromosomal Loop Domains Direct the Recombination of Antigen Receptor Genes. Cell 2015; 163:947-59. PubMed
  • Dong J, Panchakshari RA, Zhang T, Zhang Y, Hu J, Volpi SA, Meyers RM, Ho YJ, Du Z, Robbiani DF, Meng F, Gostissa M, Nussenzweig MC, Manis JP, Alt FW. Orientation-specific joining of AID-initiated DNA breaks promotes antibody class switching. Nature 2015; 525:134-9. PubMed
  • Ba Z, Meng FL, Gostissa M, Huang PY, Ke Q, Wang Z, Dao MN, Fujiwara Y, Rajewsky K, Zhang B, Alt FW. A Rapid Embryonic Stem Cell-Based Mouse Model for B-cell Lymphomas Driven by Epstein-Barr Virus Protein LMP1. Cancer Immunol Res 2015; 3:641-9. PubMed
  • Jiang W, Lee BJ, Li C, Dubois RL, Gostissa M, Alt FW, Zha S. Aberrant TCRδ rearrangement underlies the T-cell lymphocytopenia and t(12;14) translocation associated with ATM deficiency. Blood 2015. PubMed
  • Lin SG, Guo C, Su A, Zhang Y, Alt FW. CTCF-binding elements 1 and 2 in the Igh intergenic control region cooperatively regulate V(D)J recombination. Proc Natl Acad Sci U S A 2015; 112:1815-20. PubMed
  • Frock RL, Hu J, Meyers RM, Ho YJ, Kii E, Alt FW. Genome-wide detection of DNA double-stranded breaks induced by engineered nucleases. Nat Biotechnol 2015; 33:179-86. PubMed
  • Meng FL, Du Z, Federation A, Hu J, Wang Q, Kieffer-Kwon KR, Meyers RM, Amor C, Wasserman CR, Neuberg D, Casellas R, Nussenzweig MC, Bradner JE, Liu XS, Alt FW. Convergent transcription at intragenic super-enhancers targets AID-initiated genomic instability. Cell 2014; 159:1538-48. PubMed
  • Tepsuporn S, Hu J, Gostissa M, Alt FW. Mechanisms that can promote peripheral B-cell lymphoma in ATM-deficient mice. Cancer Immunol Res 2014. PubMed
  • Hu J, Tepsuporn S, Meyers RM, Gostissa M, Alt FW. Developmental propagation of V(D)J recombination-associated DNA breaks and translocations in mature B cells via dicentric chromosomes. Proc Natl Acad Sci U S A 2014; 111:10269-74. PubMed
  • Macdonald LE, Karow M, Stevens S, Auerbach W, Poueymirou WT, Yasenchak J, Frendewey D, Valenzuela DM, Giallourakis CC, Alt FW, Yancopoulos GD, Murphy AJ. Precise and in situ genetic humanization of 6 Mb of mouse immunoglobulin genes. Proc Natl Acad Sci U S A 2014; 111:5147-52. PubMed
  • Lee YN, Frugoni F, Dobbs K, Walter JE, Giliani S, Gennery AR, Al-Herz W, Haddad E, LeDeist F, Bleesing JH, Henderson LA, Pai SY, Nelson RP, El-Ghoneimy DH, El-Feky RA, Reda SM, Hossny E, Soler-Palacin P, Fuleihan RL, Patel NC, Massaad MJ, Geha RS, Puck JM, Palma P, Cancrini C, Chen K, Vihinen M, Alt FW, Notarangelo LD. A systematic analysis of recombination activity and genotype-phenotype correlation in human recombination-activating gene 1 deficiency. J Allergy Clin Immunol 2014; 133:1099-108. PubMed
  • Kumar V, Alt FW, Oksenych V. Functional overlaps between XLF and the ATM-dependent DNA double strand break response. DNA Repair (Amst) 2014; 16C:11-22. PubMed
  • Gostissa M, Schwer B, Chang A, Dong J, Meyers RM, Marecki GT, Choi VW, Chiarle R, Zarrin AA, Alt FW. IgH class switching exploits a general property of two DNA breaks to be joined in cis over long chromosomal distances. Proc Natl Acad Sci U S A 2014; 111:2644-9. PubMed
  • Shin J, He M, Liu Y, Paredes S, Villanova L, Brown K, Qiu X, Nabavi N, Mohrin M, Wojnoonski K, Li P, Cheng HL, Murphy AJ, Valenzuela DM, Luo H, Kapahi P, Krauss R, Mostoslavsky R, Yancopoulos GD, Alt FW, Chua KF, Chen D. SIRT7 represses Myc activity to suppress ER stress and prevent fatty liver disease. Cell Rep 2013; 5:654-65. PubMed
  • Wesemann DR, Portuguese AJ, Meyers RM, Gallagher MP, Cluff-Jones K, Magee JM, Panchakshari RA, Rodig SJ, Kepler TB, Alt FW. Microbial colonization influences early B-lineage development in the gut lamina propria. Nature 2013; 501:112-5. PubMed
  • Medvedovic J, Ebert A, Tagoh H, Tamir IM, Schwickert TA, Novatchkova M, Sun Q, Huis In 't Veld PJ, Guo C, Yoon HS, Denizot Y, Holwerda SJ, de Laat W, Cogné M, Shi Y, Alt FW, Busslinger M. Flexible long-range loops in the VH gene region of the Igh locus facilitate the generation of a diverse antibody repertoire. Immunity 2013; 39:229-44. PubMed
  • Callen E, Di Virgilio M, Kruhlak MJ, Nieto-Soler M, Wong N, Chen HT, Faryabi RB, Polato F, Santos M, Starnes LM, Wesemann DR, Lee JE, Tubbs A, Sleckman BP, Daniel JA, Ge K, Alt FW, Fernandez-Capetillo O, Nussenzweig MC, Nussenzweig A. 53BP1 mediates productive and mutagenic DNA repair through distinct phosphoprotein interactions. Cell 2013; 153:1266-80. PubMed
  • Alt F, Almouzni G. Genome architecture and expression. Curr Opin Genet Dev 2013. PubMed
  • Rass E, Chandramouly G, Zha S, Alt FW, Xie A. Ataxia telangiectasia mutated (ATM) is dispensable for endonuclease I-SceI-induced homologous recombination in mouse embryonic stem cells. J Biol Chem 2013; 288:7086-95. PubMed
  • Gostissa M, Bianco JM, Malkin DJ, Kutok JL, Rodig SJ, Morse HC, Bassing CH, Alt FW. Conditional inactivation of p53 in mature B cells promotes generation of nongerminal center-derived B-cell lymphomas. Proc Natl Acad Sci U S A 2013; 110:2934-9. PubMed
  • Oksenych V, Kumar V, Liu X, Guo C, Schwer B, Zha S, Alt FW. Functional redundancy between the XLF and DNA-PKcs DNA repair factors in V(D)J recombination and nonhomologous DNA end joining. Proc Natl Acad Sci U S A 2013; 110:2234-9. PubMed
  • Shi W, Bain AL, Schwer B, Al-Ejeh F, Smith C, Wong L, Chai H, Miranda MS, Ho U, Kawaguchi M, Miura Y, Finnie JW, Wall M, Heierhorst J, Wicking C, Spring KJ, Alt FW, Khanna KK. Essential developmental, genomic stability, and tumour suppressor functions of the mouse orthologue of hSSB1/NABP2. PLoS Genet. 2013; 9:e1003298. PubMed
  • Selimyan R, Gerstein RM, Ivanova I, Precht P, Subrahmanyam R, Perlot T, Alt FW, Sen R. Localized DNA demethylation at recombination intermediates during immunoglobulin heavy chain gene assembly. PLoS Biol. 2013; 11:e1001475. PubMed
  • Subrahmanyam R, Du H, Ivanova I, Chakraborty T, Ji Y, Zhang Y, Alt FW, Schatz DG, Sen R. Localized epigenetic changes induced by DH recombination restricts recombinase to DJH junctions. Nat Immunol 2012; 13:1205-12. PubMed
  • Wesemann DR, Portuguese AJ, Magee JM, Gallagher MP, Zhou X, Panchakshari RA, Alt FW. Reprogramming IgH isotype-switched B cells to functional-grade induced pluripotent stem cells. Proc Natl Acad Sci U S A 2012; 109:13745-50. PubMed
  • Guo C, Alt FW, Giallourakis C. PAIRing for distal Igh locus V(D)J recombination. Immunity 2011; 34:139-41. PubMed
  • Eccleston J, Yan C, Yuan K, Alt FW, Selsing E. Mismatch repair proteins MSH2, MLH1, and EXO1 are important for class-switch recombination events occurring in B cells that lack nonhomologous end joining. J Immunol 2011; 186:2336-43. PubMed
  • Green MR, Monti S, Dalla-Favera R, Pasqualucci L, Walsh NC, Schmidt-Supprian M, Kutok JL, Rodig SJ, Neuberg DS, Rajewsky K, Golub TR, Alt FW, Shipp MA, Manis JP. Signatures of murine B-cell development implicate Yy1 as a regulator of the germinal center-specific program. Proc Natl Acad Sci U S A 2011; 108:2873-8. PubMed
  • Basu U, Meng FL, Keim C, Grinstein V, Pefanis E, Eccleston J, Zhang T, Myers D, Wasserman CR, Wesemann DR, Januszyk K, Gregory RI, Deng H, Lima CD, Alt FW. The RNA exosome targets the AID cytidine deaminase to both strands of transcribed duplex DNA substrates. Cell 2011; 144:353-63. PubMed
  • Zha S, Jiang W, Fujiwara Y, Patel H, Goff PH, Brush JW, Dubois RL, Alt FW. Ataxia telangiectasia-mutated protein and DNA-dependent protein kinase have complementary V(D)J recombination functions. Proc Natl Acad Sci U S A 2011; 108:2028-33. PubMed
  • Zha S, Guo C, Boboila C, Oksenych V, Cheng HL, Zhang Y, Wesemann DR, Yuen G, Patel H, Goff PH, Dubois RL, Alt FW. ATM damage response and XLF repair factor are functionally redundant in joining DNA breaks. Nature 2011; 469:250-4. PubMed
  • Gostissa M, Alt FW, Chiarle R. Mechanisms that promote and suppress chromosomal translocations in lymphocytes. Annu Rev Immunol 2011; 29:319-50. PubMed
  • Giallourakis CC, Franklin A, Guo C, Cheng HL, Yoon HS, Gallagher M, Perlot T, Andzelm M, Murphy AJ, Macdonald LE, Yancopoulos GD, Alt FW. Elements between the IgH variable (V) and diversity (D) clusters influence antisense transcription and lineage-specific V(D)J recombination. Proc Natl Acad Sci U S A 2010; 107:22207-12. PubMed
  • Schwer B, Schumacher B, Lombard DB, Xiao C, Kurtev MV, Gao J, Schneider JI, Chai H, Bronson RT, Tsai LH, Deng CX, Alt FW. Neural sirtuin 6 (Sirt6) ablation attenuates somatic growth and causes obesity. Proc Natl Acad Sci U S A 2011; 107:21790-4. PubMed
  • Shimazu T, Hirschey MD, Hua L, Dittenhafer-Reed KE, Schwer B, Lombard DB, Li Y, Bunkenborg J, Alt FW, Denu JM, Jacobson MP, Verdin E. SIRT3 deacetylates mitochondrial 3-hydroxy-3-methylglutaryl CoA synthase 2 and regulates ketone body production. Cell Metab 2010; 12:654-61. PubMed
  • De Ravin SS, Cowen EW, Zarember KA, Whiting-Theobald NL, Kuhns DB, Sandler NG, Douek DC, Pittaluga S, Poliani PL, Lee YN, Notarangelo LD, Wang L, Alt FW, Kang EM, Milner JD, Niemela JE, Fontana-Penn M, Sinal SH, Malech HL. Hypomorphic Rag mutations can cause destructive midline granulomatous disease. Blood 2010; 116:1263-71. PubMed
  • Zha S, Bassing CH, Sanda T, Brush JW, Patel H, Goff PH, Murphy MM, Tepsuporn S, Gatti RA, Look AT, Alt FW. ATM-deficient thymic lymphoma is associated with aberrant tcrd rearrangement and gene amplification. J Exp Med 2010; 207:1369-80. PubMed
  • Walter JE, Rucci F, Patrizi L, Recher M, Regenass S, Paganini T, Keszei M, Pessach I, Lang PA, Poliani PL, Giliani S, Al-Herz W, Cowan MJ, Puck JM, Bleesing J, Niehues T, Schuetz C, Malech H, DeRavin SS, Facchetti F, Gennery AR, Andersson E, Kamani NR, Sekiguchi J, Alenezi HM, Chinen J, Dbaibo G, ElGhazali G, Fontana A, Pasic S, Detre C, Terhorst C, Alt FW, Notarangelo LD. Expansion of immunoglobulin-secreting cells and defects in B cell tolerance in Rag-dependent immunodeficiency. J Exp Med 2010; 207:1541-54. PubMed
  • Westerberg LS, Meelu P, Baptista M, Eston MA, Adamovich DA, Cotta-de-Almeida V, Seed B, Rosen MK, Vandenberghe P, Thrasher AJ, Klein C, Alt FW, Snapper SB. Activating WASP mutations associated with X-linked neutropenia result in enhanced actin polymerization, altered cytoskeletal responses, and genomic instability in lymphocytes. J Exp Med 2010; 207:1145-52. PubMed
  • Hirschey MD, Shimazu T, Goetzman E, Jing E, Schwer B, Lombard DB, Grueter CA, Harris C, Biddinger S, Ilkayeva OR, Stevens RD, Li Y, Saha AK, Ruderman NB, Bain JR, Newgard CB, Farese RV, Alt FW, Kahn CR, Verdin E. SIRT3 regulates mitochondrial fatty-acid oxidation by reversible enzyme deacetylation. Nature 2010; 464:121-5. PubMed
  • Zhang T, Franklin A, Boboila C, McQuay A, Gallagher MP, Manis JP, Khamlichi AA, Alt FW. Downstream class switching leads to IgE antibody production by B lymphocytes lacking IgM switch regions. Proc Natl Acad Sci U S A 2010; 107:3040-5. PubMed
  • Boboila C, Jankovic M, Yan CT, Wang JH, Wesemann DR, Zhang T, Fazeli A, Feldman L, Nussenzweig A, Nussenzweig M, Alt FW. Alternative end-joining catalyzes robust IgH locus deletions and translocations in the combined absence of ligase 4 and Ku70. Proc Natl Acad Sci U S A 2010; 107:3034-9. PubMed
  • Rucci F, Notarangelo LD, Fazeli A, Patrizi L, Hickernell T, Paganini T, Coakley KM, Detre C, Keszei M, Walter JE, Feldman L, Cheng HL, Poliani PL, Wang JH, Balter BB, Recher M, Andersson EM, Zha S, Giliani S, Terhorst C, Alt FW, Yan CT. Homozygous DNA ligase IV R278H mutation in mice leads to leaky SCID and represents a model for human LIG4 syndrome. Proc Natl Acad Sci U S A 2010; 107:3024-9. PubMed
  • Boboila C, Yan C, Wesemann DR, Jankovic M, Wang JH, Manis J, Nussenzweig A, Nussenzweig M, Alt FW. Alternative end-joining catalyzes class switch recombination in the absence of both Ku70 and DNA ligase 4. J Exp Med 2010; 207:417-27. PubMed
  • Perlot T, Pawlitzky I, Manis JP, Zarrin AA, Brodeur PH, Alt FW. Analysis of mice lacking DNaseI hypersensitive sites at the 5' end of the IgH locus. PLoS ONE 2010; 5:e13992. PubMed
  • Zhang Y, Gostissa M, Hildebrand DG, Becker MS, Boboila C, Chiarle R, Lewis S, Alt FW. The role of mechanistic factors in promoting chromosomal translocations found in lymphoid and other cancers. Adv Immunol 2010; 106:93-133. PubMed
  • Gostissa M, Yan CT, Bianco JM, Cogné M, Pinaud E, Alt FW. Long-range oncogenic activation of Igh-c-myc translocations by the Igh 3' regulatory region. Nature 2009; 462:803-7. PubMed
  • Lee YN, Alt FW, Reyes J, Gleason M, Zarrin AA, Jung D. Differential utilization of T cell receptor TCR alpha/TCR delta locus variable region gene segments is mediated by accessibility. Proc Natl Acad Sci U S A 2009; 106:17487-92. PubMed
  • Schwer B, Eckersdorff M, Li Y, Silva JC, Fermin D, Kurtev MV, Giallourakis C, Comb MJ, Alt FW, Lombard DB. Calorie restriction alters mitochondrial protein acetylation. Aging Cell 2009; 8:604-6. PubMed
  • Zha S, Boboila C, Alt FW. Mre11: roles in DNA repair beyond homologous recombination. Nat Struct Mol Biol 2009; 16:798-800. PubMed
  • Wang JH, Gostissa M, Yan CT, Goff P, Hickernell T, Hansen E, Difilippantonio S, Wesemann DR, Zarrin AA, Rajewsky K, Nussenzweig A, Alt FW. Mechanisms promoting translocations in editing and switching peripheral B cells. Nature 2009; 460:231-6. PubMed
  • Basu U,Franklin A,Schwer B,Cheng HL,Chaudhuri J,Alt FW. Regulation of activation-induced cytidine deaminase DNA deamination activity in B-cells by Ser38 phosphorylation. Biochem Soc Trans 2009; 37:561-8. PubMed
  • Callen E,Jankovic M,Wong N,Zha S,Chen HT,Difilippantonio S,Di Virgilio M,Heidkamp G,Alt FW,Nussenzweig A,Nussenzweig M. Essential role for DNA-PKcs in DNA double-strand break repair and apoptosis in ATM-deficient lymphocytes. Mol Cell 2009; 34:285-97. PubMed
  • Carpenter AC,Yang-Iott KS,Chao LH,Nuskey B,Whitlow S,Alt FW,Bassing CH. Assembled DJbeta complexes influence TCRbeta chain selection and peripheral Vbeta repertoire. J Immunol 2009; 182:5586-95. PubMed
  • Giblin W,Chatterji M,Westfield G,Masud T,Theisen B,Cheng HL,DeVido J,Alt FW,Ferguson DO,Schatz DG,Sekiguchi J. Leaky severe combined immunodeficiency and aberrant DNA rearrangements due to a hypomorphic RAG1 mutation. Blood 2009; 113:2965-75. PubMed
  • Basu U,Franklin A,Alt FW. Post-translational regulation of activation-induced cytidine deaminase. Philos Trans R Soc Lond B Biol Sci 2008; 364:667-73. PubMed
  • Cheng HL,Vuong BQ,Basu U,Franklin A,Schwer B,Astarita J,Phan RT,Datta A,Manis J,Alt FW,Chaudhuri J. Integrity of the AID serine-38 phosphorylation site is critical for class switch recombination and somatic hypermutation in mice. Proc Natl Acad Sci U S A 2009; 106:2717-22. PubMed
  • Gostissa M,Ranganath S,Bianco JM,Alt FW. Chromosomal location targets different MYC family gene members for oncogenic translocations. Proc Natl Acad Sci U S A 2009; 106:2265-70. PubMed
  • Schenten D,Kracker S,Esposito G,Franco S,Klein U,Murphy M,Alt FW,Rajewsky K. Pol zeta ablation in B cells impairs the germinal center reaction, class switch recombination, DNA break repair, and genome stability. J Exp Med 2009; 206:477-90. PubMed
  • Van Gool F,Galli M,Gueydan C,Kruys V,Prevot PP,Bedalov A,Mostoslavsky R,Alt FW,De Smedt T,Leo O. Intracellular NAD levels regulate tumor necrosis factor protein synthesis in a sirtuin-dependent manner. Nat Med 2009; 15:206-10. PubMed
  • Wang JH,Alt FW,Gostissa M,Datta A,Murphy M,Alimzhanov MB,Coakley KM,Rajewsky K,Manis JP,Yan CT. Oncogenic transformation in the absence of Xrcc4 targets peripheral B cells that have undergone editing and switching. J Exp Med 2008; 205:3079-90. PubMed
  • Oberdoerffer P,Michan S,McVay M,Mostoslavsky R,Vann J,Park SK,Hartlerode A,Stegmuller J,Hafner A,Loerch P,Wright SM,Mills KD,Bonni A,Yankner BA,Scully R,Prolla TA,Alt FW,Sinclair DA. SIRT1 redistribution on chromatin promotes genomic stability but alters gene expression during aging. Cell 2008; 135:907-18. PubMed
  • Basu U,Wang Y,Alt FW. Evolution of phosphorylation-dependent regulation of activation-induced cytidine deaminase. Mol Cell 2008; 32:285-91. PubMed
  • Li G,Alt FW,Cheng HL,Brush JW,Goff PH,Murphy MM,Franco S,Zhang Y,Zha S. Lymphocyte-specific compensation for XLF/cernunnos end-joining functions in V(D)J recombination. Mol Cell 2008; 31:631-40. PubMed
  • Bassing CH,Whitlow S,Mostoslovasky R,Yang-Iott K,Ranganath S,Alt FW. Vbeta cluster sequences reduce the frequency of primary Vbeta2 and Vbeta14 rearrangements. Eur J Immunol 2008; 38:2564-72. PubMed
  • Takizawa M,Tolarova H,Li Z,Dubois W,Lim S,Callen E,Franco S,Mosaico M,Feigenbaum L,Alt FW,Nussenzweig A,Potter M,Casellas R. AID expression levels determine the extent of cMyc oncogenic translocations and the incidence of B cell tumor development. J Exp Med 2008; 205:1949-57. PubMed
  • Zha S,Sekiguchi J,Brush JW,Bassing CH,Alt FW. Complementary functions of ATM and H2AX in development and suppression of genomic instability. Proc Natl Acad Sci U S A 2008; 105:9302-6. PubMed
  • Zarrin AA,Goff PH,Senger K,Alt FW. Sgamma3 switch sequences function in place of endogenous Sgamma1 to mediate antibody class switching. J Exp Med 2008; 205:1567-72. PubMed
  • Walkley CR,Qudsi R,Sankaran VG,Perry JA,Gostissa M,Roth SI,Rodda SJ,Snay E,Dunning P,Fahey FH,Alt FW,McMahon AP,Orkin SH. Conditional mouse osteosarcoma, dependent on p53 loss and potentiated by loss of Rb, mimics the human disease. Genes Dev 2008; 22:1662-76. PubMed
  • Franco S, Murphy MM, Li G, Borjeson T, Boboila C, Alt FW. DNA-PKcs and Artemis function in the end-joining phase of immunoglobulin heavy chain class switch recombination. J Exp Med 2008; 205:557-64. PubMed
  • Perlot T, Li G, Alt FW. Antisense transcripts from immunoglobulin heavy-chain locus V(D)J and switch regions. Proc Natl Acad Sci U S A 2008; 105:3843-8. PubMed
  • Lee IH, Cao L, Mostoslavsky R, Lombard DB, Liu J, Bruns NE, Tsokos M, Alt FW, Finkel T. A role for the NAD-dependent deacetylase Sirt1 in the regulation of autophagy. Proc Natl Acad Sci U S A 2008; 105:3374-9. PubMed
  • Zhang Y, Kwon S, Yamaguchi T, Cubizolles F, Rousseaux S, Kneissel M, Cao C, Li N, Cheng HL, Chua K, Lombard D, Mizeracki A, Matthias G, Alt FW, Khochbin S, Matthias P. Mice lacking histone deacetylase 6 have hyperacetylated tubulin but are viable and develop normally. Mol Cell Biol 2008; 28:1688-701. PubMed
  • Bassing CH, Ranganath S, Murphy M, Savic V, Gleason M, Alt FW. Aberrant V(D)J recombination is not required for rapid development of H2ax/p53-deficient thymic lymphomas with clonal translocations. Blood 2007; 111:2163-9. PubMed
  • Ranganath S, Carpenter AC, Gleason M, Shaw AC, Bassing CH, Alt FW. Productive coupling of accessible Vbeta14 segments and DJbeta complexes determines the frequency of Vbeta14 rearrangement. J Immunol 2008; 180:2339-46. PubMed
  • Lombard DB, Schwer B, Alt FW, Mostoslavsky R. SIRT6 in DNA repair, metabolism and ageing. J Intern Med 2008; 263:128-41. PubMed
  • Takeyama K, Monti S, Manis JP, Cin PD, Getz G, Beroukhim R, Dutt S, Aster JC, Alt FW, Golub TR, Shipp MA. Integrative analysis reveals 53BP1 copy loss and decreased expression in a subset of human diffuse large B-cell lymphomas. Oncogene 2008; 27:318-22. PubMed
  • Lombard DB, Alt FW, Cheng HL, Bunkenborg J, Streeper RS, Mostoslavsky R, Kim J, Yancopoulos G, Valenzuela D, Murphy A, Yang Y, Chen Y, Hirschey MD, Bronson RT, Haigis M, Guarente LP, Farese RV, Weissman S, Verdin E, Schwer B. Mammalian Sir2 homolog SIRT3 regulates global mitochondrial lysine acetylation. Mol Cell Biol 2007; 27:8807-14. PubMed
  • Wuerffel R, Wang L, Grigera F, Manis J, Selsing E, Perlot T, Alt FW, Cogne M, Pinaud E, Kenter AL. S-S synapsis during class switch recombination is promoted by distantly located transcriptional elements and activation-induced deaminase. Immunity 2007; 27:711-22. PubMed
  • Alt FW. From gene amplification to V(D)J recombination and back: a personal account of my early years in B cell biology. Eur J Immunol 2007; 37 Suppl 1:S138-47. PubMed
  • Potente M, Ghaeni L, Baldessari D, Mostoslavsky R, Rossig L, Dequiedt F, Haendeler J, Mione M, Dejana E, Alt FW, Zeiher AM, Dimmeler S. SIRT1 controls endothelial angiogenic functions during vascular growth. Genes Dev 2007; 21:2644-58. PubMed
  • Yan CT, Boboila C, Souza EK, Franco S, Hickernell TR, Murphy M, Gumaste S, Geyer M, Zarrin AA, Manis JP, Rajewsky K, Alt FW. IgH class switching and translocations use a robust non-classical end-joining pathway. Nature 2007; 449:478-82. PubMed
  • Fraenkel S, Mostoslavsky R, Novobrantseva TI, Pelanda R, Chaudhuri J, Esposito G, Jung S, Alt FW, Rajewsky K, Cedar H, Bergman Y. Allelic 'choice' governs somatic hypermutation in vivo at the immunoglobulin kappa-chain locus. Nat Immunol 2007; 8:715-22. PubMed
  • Gerhart-Hines Z, Rodgers JT, Bare O, Lerin C, Kim SH, Mostoslavsky R, Alt FW, Wu Z, Puigserver P. Metabolic control of muscle mitochondrial function and fatty acid oxidation through SIRT1/PGC-1alpha. EMBO J 2007; 26:1913-23. PubMed
  • Zha S, Alt FW, Cheng HL, Brush JW, Li G. Defective DNA repair and increased genomic instability in Cernunnos-XLF-deficient murine ES cells. Proc Natl Acad Sci U S A 2007; 104:4518-23. PubMed
  • Wu C, Ranganath S, Gleason M, Woodman BB, Borjeson TM, Alt FW, Bassing CH. Restriction of endogenous T cell antigen receptor beta rearrangements to Vbeta14 through selective recombination signal sequence modifications. Proc Natl Acad Sci U S A 2007; 104:4002-7. PubMed
  • Zarrin AA, Del Vecchio C, Tseng E, Gleason M, Zarin P, Tian M, Alt FW. Antibody class switching mediated by yeast endonuclease-generated DNA breaks. Science 2006; 315:377-81. PubMed
  • Basu U, Chaudhuri J, Phan RT, Datta A, Alt FW. Regulation of activation induced deaminase via phosphorylation. Adv Exp Med Biol 2007; 596:129-37. PubMed
  • Mostoslavsky G, Fabian AJ, Rooney S, Alt FW, Mulligan RC. Complete correction of murine Artemis immunodeficiency by lentiviral vector-mediated gene transfer. Proc Natl Acad Sci U S A 2006; 103:16406-11. PubMed
  • Franco S, Alt FW, Manis JP. Pathways that suppress programmed DNA breaks from progressing to chromosomal breaks and translocations. DNA Repair (Amst) 2006; 5:1030-41. PubMed
  • Haigis MC, Mostoslavsky R, Haigis KM, Fahie K, Christodoulou DC, Murphy AJ, Valenzuela DM, Yancopoulos GD, Karow M, Blander G, Wolberger C, Prolla TA, Weindruch R, Alt FW, Guarente L. SIRT4 inhibits glutamate dehydrogenase and opposes the effects of calorie restriction in pancreatic beta cells. Cell 2006; 126:941-54. PubMed
  • Aifantis I, Bassing CH, Garbe AI, Sawai K, Alt FW, von Boehmer H. The E delta enhancer controls the generation of CD4- CD8- alphabetaTCR-expressing T cells that can give rise to different lineages of alphabeta T cells. J Exp Med 2006; 203:1543-50. PubMed
  • Yan CT, Kaushal D, Murphy M, Zhang Y, Datta A, Chen C, Monroe B, Mostoslavsky G, Coakley K, Gao Y, Mills KD, Fazeli AP, Tepsuporn S, Hall G, Mulligan R, Fox E, Bronson R, De Girolami U, Lee C, Alt FW. XRCC4 suppresses medulloblastomas with recurrent translocations in p53-deficient mice. Proc Natl Acad Sci U S A 2006; 103:7378-83. PubMed
  • Morales JC, Franco S, Murphy MM, Bassing CH, Mills KD, Adams MM, Walsh NC, Manis JP, Rassidakis GZ, Alt FW, Carpenter PB. 53BP1 and p53 synergize to suppress genomic instability and lymphomagenesis. Proc Natl Acad Sci U S A 2006; 103:3310-5. PubMed
  • Mostoslavsky R, Chua KF, Lombard DB, Pang WW, Fischer MR, Gellon L, Liu P, Mostoslavsky G, Franco S, Murphy MM, Mills KD, Patel P, Hsu JT, Hong AL, Ford E, Cheng HL, Kennedy C, Nunez N, Bronson R, Frendewey D, Auerbach W, Valenzuela D, Karow M, Hottiger MO, Hursting S, Barrett JC, Guarente L, Mulligan R, Demple B, Yancopoulos GD, Alt FW. Genomic instability and aging-like phenotype in the absence of mammalian SIRT6. Cell 2006; 124:315-29. PubMed
  • Franco S, Gostissa M, Zha S, Lombard DB, Murphy MM, Zarrin AA, Yan C, Tepsuporn S, Morales JC, Adams MM, Lou Z, Bassing CH, Manis JP, Chen J, Carpenter PB, Alt FW. H2AX prevents DNA breaks from progressing to chromosome breaks and translocations. Mol Cell 2006; 21:201-14. PubMed
  • Jung D, Giallourakis C, Mostoslavsky R, Alt FW. Mechanism and control of V(D)J recombination at the immunoglobulin heavy chain locus. Annu Rev Immunol 2006; 24:541-70. PubMed
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