DF/HCC Program Affiliation

Lung Cancer
Breast Cancer
Leukemia

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

• 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 Apr 12.
  17431503
• 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 Apr 20;129(2):289-301
  17412408
• 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 Apr;27(8):3098-108.
  17296736
• Chen CC, Taniguchi T, D'Andrea A.The Fanconi anemia (FA) pathway confers glioma resistance to DNA alkylating agents.J Mol Med 2007 Jan 13.
  17221219
• 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 2007 Jan 19;282(3):2047-55.
  17082180
• Huang TT, D'Andrea AD.HAUSP hunting the FOX(O).Nat Cell Biol 2006 Oct;8(10):1043-5.
  17013413
• 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 (A
  16990054
• 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 Sep;26(18):7005-15.
  16943440
• 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 Aug;23(4):589-96.
  16916645
• Kennedy RD, D'Andrea AD.DNA repair pathways in clinical practice: lessons from pediatric cancer susceptibility syndromes.J Clin Oncol 2006 Aug 10;24(23):3799-808.
  16896009
• Gurtan AM, D'Andrea AD.Dedicated to the core: Understanding the Fanconi anemia complex.DNA Repair (Amst) 2006 Jun 17.
  16784902
• 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 Apr;5(4):952-61.
  16648566
• Huang TT, D'Andrea AD.Regulation of DNA repair by ubiquitylation.Nat Rev Mol Cell Biol 2006 May;7(5):323-34.
  16633336
• Andreassen PR, Ho GP, D'Andrea AD.DNA damage responses and their many interactions with the replication fork.Carcinogenesis 2006 May;27(5):883-92.
  16490739
• Taniguchi T, D'Andrea AD.Molecular pathogenesis of Fanconi anemia: recent progress.Blood 2006 Jun 1;107(11):4223-33.
  16493006
• Gurtan AM, Stuckert P, D'Andrea AD.The WD40 repeats of FANCL are required for Fanconi anemia core complex assembly.J Biol Chem 2006 Apr 21;281(16):10896-905.
  16474167
• Kennedy RD, D'Andrea AD.The Fanconi Anemia/BRCA pathway: new faces in the crowd.Genes Dev 2005 Dec 15;19(24):2925-40.
  16357213
• Howlett NG, Scuric Z, D'Andrea AD, Schiestl RH.Impaired DNA double strand break repair in cells from Nijmegen breakage syndrome patients.DNA Repair (Amst) 2006 Feb 3;5(2):251-7.
  16309973
• Garcia-Higuera I, Kuang Y, Näf D, Wasik J, D'Andrea AD.Fanconi anemia proteins FANCA, FANCC, and FANCG/XRCC9 interact in a functional nuclear complex.Mol Cell Biol 1999 Jul;19(7):4866-73.
  10373536
• Yamashita T, Kupfer GM, Naf D, Suliman A, Joenje H, Asano S, D'Andrea AD.The fanconi anemia pathway requires FAA phosphorylation and FAA/FAC nuclear accumulation.Proc Natl Acad Sci U S A 1998 Oct 27;95(22):13085-90.
  9789045