Photo of Alan D. D'Andrea,  MD

Alan D. D'Andrea, MD

Dana-Farber Cancer Institute

Dana-Farber Cancer Institute
Phone: (617) 632-2112
Fax: (617) 632-5757


alan_dandrea@dfci.harvard.edu

Alan D. D'Andrea, MD

Dana-Farber Cancer Institute

EDUCATIONAL TITLES

  • Alvan T. and Viola D. Fuller American Cancer Society Professor of Radiation Oncology, Radiation Oncology, Harvard Medical School
  • Professor, Pediatrics, Harvard Medical School
  • Scientific Director, Molecular Diagnostics Laboratory, Dana-Farber Cancer Institute

DF/HCC PROGRAM AFFILIATION

Research Abstract

Fanconi Anema (FA) is an autosomal recessive disease characterized by progressive bone marrow failure and cancer susceptibility. Cells from patients with FA are hypersensitive to DNA-damaging agents, and the molecular defect is presumably one of DNA repair. FA has at least eight complementation groups (A-H), and three FA genes, corresponding to complementation groups A, C, and G have been cloned. We have recently demonstrated that the FANCA, FANCC, and FANCG proteins bind and form a nuclear complex, although the function of this complex remains unknown. More recently, we have demonstrated that the FANCA protein is phosphorylated and that its phosphorylation correlates with FANCC and FANCG binding and nuclear accumulation. Interestingly, other (non-A, C, G) FA cells are defective in FANCA phosphorylation, FA protein binding, and nuclear accumulation of the complex, suggesting that other FA gene products also regulate this pathway. Disruption of the pathway leads to chromosome instability and leukemia. On-going projects include the identification and cloining of other proteins in the FA complex and the biochemical assessment of the function of the nuclear FA complex.

Publications

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  • Howitt BE, Shukla SA, Sholl LM, Ritterhouse LL, Watkins JC, Rodig S, Stover E, Strickland KC, D'Andrea AD, Wu CJ, Matulonis UA, Konstantinopoulos PA. Association of Polymerase e-Mutated and Microsatellite-Instable Endometrial Cancers With Neoantigen Load, Number of Tumor-Infiltrating Lymphocytes, and Expression of PD-1 and PD-L1. JAMA Oncol 2015. PubMed
  • Xie J, Kim H, Moreau LA, Puhalla S, Garber J, Al Abo M, Takeda S, D'Andrea AD. RNF4-mediated polyubiquitination regulates the Fanconi anemia/BRCA pathway. J Clin Invest 2015; 125:1523-32. PubMed
  • Ceccaldi R, O'Connor KW, Mouw KW, Li AY, Matulonis UA, D'Andrea AD, Konstantinopoulos PA. A unique subset of epithelial ovarian cancers with platinum sensitivity and PARP inhibitor resistance. Cancer Res 2015; 75:628-34. PubMed
  • Ceccaldi R, Liu JC, Amunugama R, Hajdu I, Primack B, Petalcorin MI, O'Connor KW, Konstantinopoulos PA, Elledge SJ, Boulton SJ, Yusufzai T, D'Andrea AD. Homologous-recombination-deficient tumours are dependent on Polθ-mediated repair. Nature 2015; 518:258-62. PubMed
  • Kushwaha D, O'Leary C, Cron KR, Deraska P, Zhu K, D'Andrea AD, Kozono D. USP9X inhibition promotes radiation-induced apoptosis in non-small cell lung cancer cells expressing mid-to-high MCL1. Cancer Biol Ther 2015; 16:392-401. PubMed
  • Wojtaszek JL, Wang S, Kim H, Wu Q, D'Andrea AD, Zhou P. Ubiquitin recognition by FAAP20 expands the complex interface beyond the canonical UBZ domain. Nucleic Acids Res 2014; 42:13997-4005. PubMed
  • Mouw KW, D'Andrea AD. Crosstalk between the nucleotide excision repair and Fanconi anemia/BRCA pathways. DNA Repair (Amst) 2014. PubMed
  • Kim H, Dejsuphong D, Adelmant G, Ceccaldi R, Yang K, Marto JA, D'Andrea AD. Transcriptional repressor ZBTB1 promotes chromatin remodeling and translesion DNA synthesis. Mol Cell 2014; 54:107-18. PubMed
  • Polito D, Cukras S, Wang X, Spence P, Moreau L, D'Andrea AD, Kee Y. The carboxyl terminus of FANCE recruits FANCD2 to the Fanconi Anemia (FA) E3 ligase complex to promote the FA DNA repair pathway. J Biol Chem 2014. PubMed
  • Mistry H, Hsieh G, Buhrlage SJ, Huang M, Park E, Cuny GD, Galinsky I, Stone RM, Gray NS, D'Andrea AD, Parmar K. Small-molecule inhibitors of USP1 target ID1 degradation in leukemic cells. Mol Cancer Ther 2013; 12:2651-62. PubMed
  • Etemadmoghadam D, Weir BA, Au-Yeung G, Alsop K, Mitchell G, George J, , Davis S, D'Andrea AD, Simpson K, Hahn WC, Bowtell DD. Synthetic lethality between CCNE1 amplification and loss of BRCA1. Proc Natl Acad Sci U S A 2013; 110:19489-94. PubMed
  • Park E, Kim JM, Primack B, Weinstock DM, Moreau LA, Parmar K, D'Andrea AD. Inactivation of Uaf1 causes defective homologous recombination and early embryonic lethality in mice. Mol Cell Biol 2013; 33:4360-70. PubMed
  • Johnson N, Johnson SF, Yao W, Li YC, Choi YE, Bernhardy AJ, Wang Y, Capelletti M, Sarosiek KA, Moreau LA, Chowdhury D, Wickramanayake A, Harrell MI, Liu JF, D'Andrea AD, Miron A, Swisher EM, Shapiro GI. Stabilization of mutant BRCA1 protein confers PARP inhibitor and platinum resistance. Proc Natl Acad Sci U S A 2013; 110:17041-6. PubMed
  • Park E, Kim H, Kim JM, Primack B, Vidal-Cardenas S, Xu Y, Price BD, Mills AA, D'Andrea AD. FANCD2 activates transcription of TAp63 and suppresses tumorigenesis. Mol Cell 2013; 50:908-18. PubMed
  • O'Connor KW, Dejsuphong D, Park E, Nicolae CM, Kimmelman AC, D'Andrea AD, Moldovan GL. PARI overexpression promotes genomic instability and pancreatic tumorigenesis. Cancer Res 2013; 73:2529-39. PubMed
  • D'Andrea AD. BRCA1: a missing link in the Fanconi anemia/BRCA pathway. 2013; 3:376-8. PubMed
  • Price BD, D'Andrea AD. Chromatin remodeling at DNA double-strand breaks. Cell 2013; 152:1344-54. PubMed
  • Cron KR, Zhu K, Kushwaha DS, Hsieh G, Merzon D, Rameseder J, Chen CC, D'Andrea AD, Kozono D. Proteasome inhibitors block DNA repair and radiosensitize non-small cell lung cancer. PLoS ONE 2013; 8:e73710. PubMed
  • Parmar K, D'Andrea AD. Stressed out: endogenous aldehydes damage hematopoietic stem cells. Cell Stem Cell 2012; 11:583-4. PubMed
  • Kee Y, D'Andrea AD. Molecular pathogenesis and clinical management of Fanconi anemia. J Clin Invest 2012; 122:3799-806. PubMed
  • Wojtaszek J, Lee CJ, D'Souza S, Minesinger B, Kim H, D'Andrea AD, Walker GC, Zhou P. Structural basis of Rev1-mediated assembly of a quaternary vertebrate translesion polymerase complex consisting of Rev1, heterodimeric polymerase (Pol) ζ, and Pol κ. J Biol Chem 2012; 287:33836-46. PubMed
  • Moldovan GL, D'Andrea AD. To the rescue: the Fanconi anemia genome stability pathway salvages replication forks. Cancer Cell 2012; 22:5-6. PubMed
  • Ceccaldi R, Parmar K, Mouly E, Delord M, Kim JM, Regairaz M, Pla M, Vasquez N, Zhang QS, Pondarre C, Peffault de Latour R, Gluckman E, Cavazzana-Calvo M, Leblanc T, Larghero J, Grompe M, Socié G, D'Andrea AD, Soulier J. Bone marrow failure in Fanconi anemia is triggered by an exacerbated p53/p21 DNA damage response that impairs hematopoietic stem and progenitor cells. Cell Stem Cell 2012; 11:36-49. PubMed
  • Jacquemont C, Simon JA, D'Andrea AD, Taniguchi T. Non-specific chemical inhibition of the Fanconi anemia pathway sensitizes cancer cells to cisplatin. Mol Cancer 2012; 11:26. PubMed
  • Alexander BM, Sprott K, Farrow DA, Wang X, D'Andrea AD, Schnitt SJ, Collins LC, Weaver DT, Garber JE. DNA repair protein biomarkers associated with time to recurrence in triple-negative breast cancer. Clin Cancer Res 2010; 16:5796-804. PubMed
  • Vinciguerra P, Godinho SA, Parmar K, Pellman D, D'Andrea AD. Cytokinesis failure occurs in Fanconi anemia pathway-deficient murine and human bone marrow hematopoietic cells. J Clin Invest 2010; 120:3834-42. PubMed
  • Kee Y, D'Andrea AD. Expanded roles of the Fanconi anemia pathway in preserving genomic stability. Genes Dev 2010; 24:1680-94. PubMed
  • Huang M, D'Andrea AD. A new nuclease member of the FAN club. Nat Struct Mol Biol 2010; 17:926-8. PubMed
  • Huang M, Kim JM, Shiotani B, Yang K, Zou L, D'Andrea AD. The FANCM/FAAP24 complex is required for the DNA interstrand crosslink-induced checkpoint response. Mol Cell 2010; 39:259-68. PubMed
  • Parmar K, Kim J, Sykes SM, Shimamura A, Stuckert P, Zhu K, Hamilton A, Deloach MK, Kutok JL, Akashi K, Gilliland DG, D'Andrea A. Hematopoietic Stem Cell Defects in Mice with Deficiency of Fancd2 or Usp1. Stem Cells 2010; 28:1186-95. PubMed
  • Yang K, Moldovan GL, D'Andrea AD. RAD18-dependent recruitment of SNM1A to DNA repair complexes by a ubiquitin-binding zinc finger. J Biol Chem 2010; 285:19085-91. PubMed
  • D'Andrea AD. Susceptibility pathways in Fanconi's anemia and breast cancer. N Engl J Med 2010; 362:1909-19. PubMed
  • Tulpule A, Lensch MW, Miller JD, Austin K, D'Andrea A, Schlaeger TM, Shimamura A, Daley GQ. Knockdown of Fanconi anemia genes in human embryonic stem cells reveals early developmental defects in the hematopoietic lineage. Blood 2010; 115:3453-62. PubMed
  • Kee Y, Yang K, Cohn MA, Haas W, Gygi SP, D'Andrea AD. WDR20 regulates activity of the USP12/UAF1 deubiquitinating enzyme complex. J Biol Chem 2010; 285:11252-7. PubMed
  • Lee KY, Yang K, Cohn MA, Sikdar N, D'Andrea AD, Myung K. Human ELG1 regulates the level of ubiquitinated proliferating cell nuclear antigen (PCNA) through its interactions with PCNA and USP1. J Biol Chem 2010; 285:10362-9. PubMed
  • Moldovan GL, Madhavan MV, Mirchandani KD, McCaffrey RM, Vinciguerra P, D'Andrea AD. DNA polymerase POLN participates in cross-link repair and homologous recombination. Mol Cell Biol 2010; 30:1088-96. PubMed
  • Vinciguerra P, D'Andrea AD. FANCM: A landing pad for the Fanconi Anemia and Bloom's Syndrome complexes. Mol Cell 2010; 36:916-7. PubMed
  • Moldovan GL, D'Andrea AD. FANCD2 hurdles the DNA interstrand crosslink. Cell 2010; 139:1222-4. PubMed
  • Johnson N, Cai D, Kennedy RD, Pathania S, Arora M, Li YC, D'Andrea AD, Parvin JD, Shapiro GI. Cdk1 participates in BRCA1-dependent S phase checkpoint control in response to DNA damage. Mol Cell 2009; 35:327-39. PubMed
  • Kee Y,Kim JM,D'Andrea AD. Regulated degradation of FANCM in the Fanconi anemia pathway during mitosis. Genes Dev 2009; 23:555-60. PubMed
  • Cohn MA,Kee Y,Haas W,Gygi SP,D'Andrea AD. UAF1 is a subunit of multiple deubiquitinating enzyme complexes. J Biol Chem 2008; 284:5343-51. PubMed
  • Kim JM,Parmar K,Huang M,Weinstock DM,Ruit CA,Kutok JL,D'Andrea AD. Inactivation of murine Usp1 results in genomic instability and a Fanconi anemia phenotype. Dev Cell 2009; 16:314-20. PubMed
  • Cohn MA,D'Andrea AD. Chromatin recruitment of DNA repair proteins: lessons from the fanconi anemia and double-strand break repair pathways. Mol Cell 2008; 32:306-12. PubMed
  • Mirchandani KD, McCaffrey RM, D'Andrea AD. The Fanconi anemia core complex is required for efficient point mutagenesis and Rev1 foci assembly. DNA Repair (Amst) 2008; 7:902-11. PubMed
  • Sidi S, Sanda T, Kennedy RD, Hagen AT, Jette CA, Hoffmans R, Pascual J, Imamura S, Kishi S, Amatruda JF, Kanki JP, Green DR, D'Andrea AA, Look AT. Chk1 suppresses a caspase-2 apoptotic response to DNA damage that bypasses p53, Bcl-2, and caspase-3. Cell 2008; 133:864-77. PubMed
  • Kim JM, Kee Y, Gurtan A, D'Andrea AD. Cell cycle-dependent chromatin loading of the Fanconi anemia core complex by FANCM/FAAP24. Blood 2008; 111:5215-22. PubMed
  • Cohn MA, Kowal P, Yang K, Haas W, Huang TT, Gygi SP, D'Andrea AD. A UAF1-containing multisubunit protein complex regulates the Fanconi anemia pathway. Mol Cell 2007; 28:786-97. PubMed
  • Chen CC, Taniguchi T, D'Andrea A. The Fanconi anemia (FA) pathway confers glioma resistance to DNA alkylating agents. J Mol Med 2007; 85:497-509. PubMed
  • Kennedy RD, Chen CC, Stuckert P, Archila EM, De la Vega MA, Moreau LA, Shimamura A, D'Andrea AD. Fanconi anemia pathway-deficient tumor cells are hypersensitive to inhibition of ataxia telangiectasia mutated. J Clin Invest 2007; 117:1440-9. PubMed
  • Smogorzewska A, Matsuoka S, Vinciguerra P, McDonald ER, Hurov KE, Luo J, Ballif BA, Gygi SP, Hofmann K, D'Andrea AD, Elledge SJ. Identification of the FANCI Protein, a Monoubiquitinated FANCD2 Paralog Required for DNA Repair. Cell 2007; 129:289-301. PubMed
  • Wang X, Kennedy RD, Ray K, Stuckert P, Ellenberger T, D'Andrea AD. Chk1-mediated phosphorylation of FANCE is required for the Fanconi anemia/BRCA pathway. Mol Cell Biol 2007; 27:3098-108. PubMed
  • Kowal P, Gurtan AM, Stuckert P, D'Andrea AD, Ellenberger T. Structural determinants of human FANCF protein that function in the assembly of a DNA damage signaling complex. J Biol Chem 2006; 282:2047-55. PubMed
  • Chen CC, Motegi A, Hasegawa Y, Myung K, Kolodner R, D'Andrea A. Genetic analysis of ionizing radiation-induced mutagenesis in Saccharomyces cerevisiae reveals TransLesion Synthesis (TLS) independent of PCNA K164 SUMOylation and ubiquitination. DNA Repair (Amst) 2006; 5:1475-88. PubMed
  • Huang TT, D'Andrea AD. HAUSP hunting the FOX(O). Nat Cell Biol 2006; 8:1043-5. PubMed
  • Gurtan AM, D'Andrea AD. Dedicated to the core: Understanding the Fanconi anemia complex. DNA Repair (Amst) 2006; 5:1119-25. PubMed
  • Ho GP, Margossian S, Taniguchi T, D'Andrea AD. Phosphorylation of FANCD2 on two novel sites is required for mitomycin C resistance. Mol Cell Biol 2006; 26:7005-15. PubMed
  • Mirchandani KD, D'Andrea AD. The Fanconi anemia/BRCA pathway: A coordinator of cross-link repair. Exp Cell Res 2006; 312:2647-53. PubMed
  • Kennedy RD, D'Andrea AD. DNA repair pathways in clinical practice: lessons from pediatric cancer susceptibility syndromes. J Clin Oncol 2006; 24:3799-808. PubMed
  • Machida YJ, Machida Y, Chen Y, Gurtan AM, Kupfer GM, D'Andrea AD, Dutta A. UBE2T is the E2 in the Fanconi anemia pathway and undergoes negative autoregulation. Mol Cell 2006; 23:589-96. PubMed
  • Taniguchi T, D'Andrea AD. Molecular pathogenesis of Fanconi anemia: recent progress. Blood 2006; 107:4223-33. PubMed
  • Andreassen PR, Ho GP, D'Andrea AD. DNA damage responses and their many interactions with the replication fork. Carcinogenesis 2006; 27:883-92. PubMed
  • Huang TT, D'Andrea AD. Regulation of DNA repair by ubiquitylation. Nat Rev Mol Cell Biol 2006; 7:323-34. PubMed
  • Gurtan AM, Stuckert P, D'Andrea AD. The WD40 repeats of FANCL are required for Fanconi anemia core complex assembly. J Biol Chem 2006; 281:10896-905. PubMed
  • Huang TT, Nijman SM, Mirchandani KD, Galardy PJ, Cohn MA, Haas W, Gygi SP, Ploegh HL, Bernards R, D'Andrea AD. Regulation of monoubiquitinated PCNA by DUB autocleavage. Nat Cell Biol 2006; 8:339-47. PubMed
  • Chirnomas D, Taniguchi T, de la Vega M, Vaidya AP, Vasserman M, Hartman AR, Kennedy R, Foster R, Mahoney J, Seiden MV, D'Andrea AD. Chemosensitization to cisplatin by inhibitors of the Fanconi anemia/BRCA pathway. Mol Cancer Ther 2006; 5:952-61. PubMed
  • Levine RL, Wadleigh M, Cools J, Ebert BL, Wernig G, Huntly BJ, Boggon TJ, Wlodarska I, Clark JJ, Moore S, Adelsperger J, Koo S, Lee JC, Gabriel S, Mercher T, D'Andrea A, Frohling S, Dohner K, Marynen P, Vandenberghe P, Mesa RA, Tefferi A, Griffin JD, Eck MJ, Sellers WR, Meyerson M, Golub TR, Lee SJ, Gilliland DG. Activating mutation in the tyrosine kinase JAK2 in polycythemia vera, essential thrombocythemia, and myeloid metaplasia with myelofibrosis. Cancer Cell 2005; 7:387-97. PubMed
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