Friday, April 26, 2024
4/26/2024
PROJECT SUMMARY Children with Fanconi anemia (FA) demonstrate developmental disorders that include short stature, musculoskeletal defects, cancer predisposition, bone marrow failure (BMF) and anemia. In a significant proportion of cases, FA is associated with biallelic mutations in the hereditary breast and ovarian cancer (HBOC) genes. Pre-clinical FA studies have largely relied on transgenic animal models. However, currently available FA mouse models are born without developmental defects and hematological abnormalities have to be chemically induced. Our laboratory has developed a new Brca1CC mutant mouse model with a 3-amino acid deletion in the coiled-coil (CC) domain of Brca1 that specifically disrupts the Brca1-Palb2 association, resulting in loss of Rad51 loading and HR deficiency. Notably, Brca1CC homozygous mice are born at sub-Mendelian ratios, and neo-natal mice demonstrate a range of phenotypes analogous to FA in humans, including short stature, BMF with severe anemia, and adult mice develop leukemia. Therefore, Brca1CC mice closely resemble human FA and provide a new tool to gain unprecedented insight into biological pathways that underpin FA etiology. Both homologous recombination (HR) and microhomology-mediated end joining (MMEJ) are double stranded DNA break (DSB) repair pathways that are initiated by DNA end resection, a process where DSBs are resected by nucleases to form single stranded (ss)DNA regions. In preliminary data, we examined human FA patient cells, as well as Brca1CC MEFs, for HR and MMEJ activity. Interestingly, while HR was lowered, MMEJ was hyperactivated in FA cell lines. We now hypothesize that hyperactive DNA end resection and MMEJ promote the molecular pathogenesis of FA. We will address the following Specific Aims: 1) identify DNA repair pathways that are hyperactive in FA; 2) uncover mechanisms that promote FA embryonic development and pathogenesis; and 3) examine the effects of MMEJ inhibition on FA pathogenesis. Collectively, the proposed experiments will yield new insight into DNA repair mechanisms that promote genome instability and FA.
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