Fanconi anemia (FA) is a genetic disorder inherited via autosomal recessive or X-linked patterns. FA patients manifest progressive bone marrow dysfunction, pancytopenia, and drastically elevated cancer predisposition. Germline mutations in 13 different Fanconi genes (FANCA - I) have been identified, each corresponding to a distinct complementation group. The hallmark of Fanconi patient cells is profoundly increased sensitivity to bifunctional alkylating agents capable of forming DNA interstrand crosslinks, suggesting an important role of the Fanconi pathway in DNA damage response. Consistent with this notion, functions of the FANC proteins seems to organize around the DNA damage-dependent monoubiquitination of FANCD2. FANCI was found to be a direct substrate of the ATM/ATR checkpoint signal initiation kinases. However, how FANC gene products help protecting cells from with crosslinked DNA remains a key question. The goal of Project 3 is to study proteins recruited to the site of DNA interstrand crosslinks and to elucidate their role in crosslink repair and damage response signaling. We hypothesis is that components of the Fanconi anemia pathway is involved in different aspects of responses to crosslinking damage. This is hypothesis is addressed by the three Specific Aims.
In Aim 1 and 2, we will use a novel approach to investigate components of the Fanconi anemia pathway for its ability to be recruited to the site of crosslink in a DNA replication-dependent and -independent manner. Candidate proteins that have been suggested to have involvement in ICL processing will also be examining for their presence at the site of the lesion. Finally, we will attempt an unbiased purification approach aimed at identify novel factor involved in crosslink processing. These studies are expected to provide significant insights toward the understanding of the Fanconi anemia pathway as well as mechanisms of ICL repair.
This (Research Project/Core) is part of a multicomponent Program Project with the theme of understanding the processing of complex DNA damage by mammalian cells. The significance to human health is to generate new knowledge and paradigms for modeling DNA repair of DNA interstrand crosslinks (ICLs), to improve therapy using ICL-inducing compounds, and to identify new therapeutic targets for cancer treatment.
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