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LARP7 is a substrate of BRCA1 that regulats genome instability and tumorigenesis

ABSTRACT: Impaired DNA repair leads to cancer, aging and many genetic diseases. However, understanding of the complexity of DNA is far from complete, resulting in the failure of therapies using genotoxic reagents. Here, we found that LARP7, an RNA-binding protein known to stabilize 7SK RNA, was degraded after DNA injury caused by ionizing radiation and chemotherapy. The LARP7 degradation was catalyzed by an E3 ligase complex of BRCA1 and BARD1 that was triggered by ATM-mediated phosphorylation. LARP7 depletion caused transcriptional repression of the cell cycle regulators CCNB1, CCNB2 and CDK1; this repression arrested cells before the G2/M DNA damage checkpoint and reduced BRCA2 phosphorylation, therefore enhancing Rad51 recruitment and ultimately ensuring the homologous repair of damaged DNA. Importantly, the increased DNA damage repair capacity induced by LARP7 depletion caused resistance to ionizing radiation and CDDP treatment in both wild-type and BRCA1-mutant breast cancer cells and in mouse xenografts. Such resistance also contributed to reduced relapse-free survival rates in breast cancer patients with low levels of LARP7 after chemotherapy. Taken together, the results of this study show that LARP7 coordinates cell cycle progression and faithful DNA repair. We suggest that this mechanism could be exploited to prevent tumorigenesis and improve the effectiveness of cancer therapies.

ORGANISM(S): Homo sapiens

PROVIDER: GSE124393 | GEO | 2019/01/01

REPOSITORIES: GEO

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