Wednesday, February 5, 2025
2/5/2025
Project Summary REV7/FANCV is a versatile DNA repair protein. It binds to REV3 in the Fanconi Anemia/BRCA pathway, and it binds to SHLD3 in the NHEJ repair pathway. REV7 has at least one additional seatbelt-binding partner, CHAMP1. CHAMP1 is a little-known but highly conserved zinc finger protein, first identified as a REV7 interactor. CHAMP1 localizes to chromosomes, recruits REV7 to spindles, and plays a role in kinetochore- microtubule interactions. Germline heterozygous mutations in CHAMP1 are associated with a rare syndromic form of intellectual disability and dysmorphic features in humans, with some cellular and clinical similarities to Fanconi Anemia, though the relevance of this disease to FA has previously been unexplored. We have very recently shown that the binding of CHAMP1 to REV7 promotes DSB end resection and HR repair (Li et al, 2022). The CHAMP1 protein binds to the seatbelt domain of REV7, thereby increasing Homologous Recombination repair and competing with the binding of SHLD3 or REV3 to REV7. CHAMP1 is a component of a large, multisubunit heterochromatin complex, containing CHAMP1, POGZ, and HP1α (the so-called CHAMP1 complex). We have shown that patient-derived mutations in the CHAMP1 protein disrupt the CHAMP1 complex and disrupt HR repair, leading to a characteristic phenotype and drug sensitivity of the peripheral blood lymphocytes of CHAMP1 patients. Interestingly, we have now shown that the CHAMP1 complex accumulates at telomeres (i.e., critical concentrated sites heterochromatin) and maintains telomere length via its HR activity. Although most human tumor cells rely on telomerase to maintain telomere length, many other human tumors use the ALT (Alternative Lengthening of Telomeres) Pathway, an HR-driven pathway, to maintain telomeres and to avoid replication senescence. Importantly, we have now shown that ALT tumor cells depend on the HR activity of the CHAMP1 complex, providing a molecular basis of the CHAMP1 syndrome. Knockdown of the CHAMP1 complex in ALT tumor cells results in accelerated telomere shortening. Accordingly, the ALT pathway and the CHAMP1 complex are now highly attractive targets for cancer therapy. The Specific Aims of the current application are to analyze the structure of the CHAMP1 complex and to determine its role in HR repair and Telomere Length Maintenance. 1
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