Fanconi Anemia (FA) is a rare inherited autosomal recessive genomic instability disorder characterized by developmental abnormalities, bone marrow failure (BMF), myelodysplastic syndrome (MDS), acute myeloblastic leukemia (AML) susceptibility, and hypersensitivity to DNA crosslinking agents. The study of this rare disease is significant because it has led to a broader understanding of BMF, MDS, and AML in the general (non-FA) population. FA patients often present with MDS or AML, with the highest frequency during their teens or young adulthood. It is estimated that 19% of FA patients present with MDS, usually exhibiting refractory cytopenia and multilineage dysplasia. There are sixteen known FA genetic subtypes, and the encoded FA proteins cooperate in a common DNA repair pathway, the so-called Fanconi Anemia/BRCA pathway (D'Andrea AD. Susceptibility pathways in Fanconi's anemia and breast cancer: 2010 N Engl J Med 362: 1909-1919). Inherited or acquired disruption of this pathway leads to the characteristic chromosome instability phenotype of FA. In the FA/BRCA pathway, DNA damage activates the assembly of at least eight of the FA proteins into a Fanconi Anemia (FA) core complex which translocates to the site of the damage. The FA core complex, in turn, monoubiquitinates the FANCD2/FANCI heterodimer at this site. Monoubiquitinated FANCD2 subsequently binds FANCP/SLX4 (an endonuclease complex), via the monoubiquitin binding pocket (UBZ4 domain) of FANCP/SLX4. FANCP/SLX4 in turn mediates the excision of the DNA crosslink. The resulting double strand break is repaired by the downstream FA proteins (D1/BRCA2, O, N). After completion of DNA repair, the FANCD2-Ub protein is deubiquitinated by USP1. The purpose of this new application is to examine novel regulatory features of the FA/BRCA pathway. During the five-year study period we plan 1) to determine the functional role of sumoylation of the Fanconi Anemia core complex in the FA/BRCA pathway, 2) to determine the functional role of new subunits of the Fanconi Anemia core complex in the FA/BRCA pathway, and 3) to determine the different roles of FANCD2 and FANCI in the FA/BRCA pathway.
Patients with the genetic disease, Fanconi Anemia (FA), develop anemia, myelodysplastic syndrome (MDS), and acute myelogenous leukemia (AML). Sixteen FA proteins cooperate in a novel DNA repair pathway. The purpose of this application is to elucidate novel regulatory features of this pathway.
| Karras, Georgios I; Yi, Song; Sahni, Nidhi et al. (2017) HSP90 Shapes the Consequences of Human Genetic Variation. Cell 168:856-866.e12 |
| Mouw, Kent W; Goldberg, Michael S; Konstantinopoulos, Panagiotis A et al. (2017) DNA Damage and Repair Biomarkers of Immunotherapy Response. Cancer Discov 7:675-693 |
| Kais, Zeina; Rondinelli, Beatrice; Holmes, Amie et al. (2016) FANCD2 Maintains Fork Stability in BRCA1/2-Deficient Tumors and Promotes Alternative End-Joining DNA Repair. Cell Rep 15:2488-99 |
| Bluteau, Dominique; Masliah-Planchon, Julien; Clairmont, Connor et al. (2016) Biallelic inactivation of REV7 is associated with Fanconi anemia. J Clin Invest 126:3580-4 |
| Ceccaldi, Raphael; Rondinelli, Beatrice; D'Andrea, Alan D (2016) Repair Pathway Choices and Consequences at the Double-Strand Break. Trends Cell Biol 26:52-64 |
| Ceccaldi, Raphael; Liu, Jessica C; Amunugama, Ravindra et al. (2015) Homologous-recombination-deficient tumours are dependent on Pol?-mediated repair. Nature 518:258-62 |
| Xie, Jenny; Kim, Hyungjin; Moreau, Lisa A et al. (2015) RNF4-mediated polyubiquitination regulates the Fanconi anemia/BRCA pathway. J Clin Invest 125:1523-32 |
| Kim, Hyungjin; Dejsuphong, Donniphat; Adelmant, Guillaume et al. (2014) Transcriptional repressor ZBTB1 promotes chromatin remodeling and translesion DNA synthesis. Mol Cell 54:107-118 |
| Choi, Young Eun; Pan, Yunfeng; Park, Eunmi et al. (2014) MicroRNAs down-regulate homologous recombination in the G1 phase of cycling cells to maintain genomic stability. Elife 3:e02445 |
| Polito, David; Cukras, Scott; Wang, Xiaozhe et al. (2014) 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 289:7003-10 |
Showing the most recent 10 out of 69 publications
