Fanconi Anemia (FA) is a rare autosomal recessive cancer susceptibility disorder characterized by development abnormalities, bone marrow failure, and cellular hypersensitivity to DNA crosslinking agents. The systematic study of cell lines derived from FA patients has led to the cloning of eight FA genes (A, C, DI/BRCA2, D2, E, F, G, L) and the elucidation of a novel DNA repair pathway (the Fanconi Anemia/BRCA pathway). The elucidation of this pathway had broad significance for the understanding of the pathogenesis of aplastic anemia and cancer in the general population.
The specific aims of this five year grant are to (i) identify the molecular sensor of the FA/BRCA pathway (ii) determine the structural etements of FANCD2 required for its functional interaction with BRCA2 in chromatin and required for its DNA repair activities, and (iii) evaluate the newly identified FA-I and FA-J complementation groups.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
5R37HL052725-19
Application #
8311811
Study Section
Special Emphasis Panel (NSS)
Program Officer
Qasba, Pankaj
Project Start
1994-08-01
Project End
2014-07-31
Budget Start
2012-08-01
Budget End
2013-07-31
Support Year
19
Fiscal Year
2012
Total Cost
$413,340
Indirect Cost
$177,146
Name
Dana-Farber Cancer Institute
Department
Type
DUNS #
076580745
City
Boston
State
MA
Country
United States
Zip Code
02215
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Mistry, Helena; Hsieh, Grace; Buhrlage, Sara J et al. (2013) Small-molecule inhibitors of USP1 target ID1 degradation in leukemic cells. Mol Cancer Ther 12:2651-62
O'Connor, Kevin W; Dejsuphong, Donniphat; Park, Eunmi et al. (2013) PARI overexpression promotes genomic instability and pancreatic tumorigenesis. Cancer Res 73:2529-39
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Kee, Younghoon; Huang, Min; Chang, Sophia et al. (2012) Inhibition of the Nedd8 system sensitizes cells to DNA interstrand cross-linking agents. Mol Cancer Res 10:369-77
Kim, Hyungjin; Yang, Kailin; Dejsuphong, Donniphat et al. (2012) Regulation of Rev1 by the Fanconi anemia core complex. Nat Struct Mol Biol 19:164-70
Moldovan, George-Lucian; Dejsuphong, Donniphat; Petalcorin, Mark I R et al. (2012) Inhibition of homologous recombination by the PCNA-interacting protein PARI. Mol Cell 45:75-86
Murai, Junko; Yang, Kailin; Dejsuphong, Donniphat et al. (2011) The USP1/UAF1 complex promotes double-strand break repair through homologous recombination. Mol Cell Biol 31:2462-9
Parmar, Kalindi; Kim, Jungmin; Sykes, Stephen M et al. (2010) Hematopoietic stem cell defects in mice with deficiency of Fancd2 or Usp1. Stem Cells 28:1186-95
Moldovan, George-Lucian; D'Andrea, Alan D (2009) FANCD2 hurdles the DNA interstrand crosslink. Cell 139:1222-4

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