National Institutes of Health 5P01CA275717-02

Project 2: BRCA1-dependent DNA End Resection and Regulation via the 53BP1 Axis

This award supports research on the mechanisms regulating DNA double strand break repair, focusing on the roles of 53BP1 and BRCA1 in DNA end resection and repair pathway choice, with implications for targeted cancer therapies.

Description

DNA double strand breaks (DSBs) are induced by genotoxic agents such as ionizing radiation, chemotherapeutic agents, and during encounters of the DNA replication machinery with DNA damage. The two major, mechanistically distinct DSB repair pathways are non-homologous DNA end joining (NHEJ) and DNA homology-directed repair (HDR). NHEJ is efficient but error-prone. HDR is inherently accurate and represents the preferred repair tool for DNA replication-associated DSBs. HDR commences with the resection of the 5’-terminated strand at break ends to generate a DNA tail that serves as the template for assembly of the RAD51 recombinase filament. DSB repair pathway choice is linked to cell cycle progression and is determined by whether or not a DSB undergoes extensive resection. Long-range resection is principally mediated by the 5’-3’ exonuclease EXO1 or the BLM helicase-DNA2 endonuclease. The chromatin reader 53BP1 nucleates the formation of a higher order ensemble that harbors the CTC1-STN1-TEN1 (CST) complex at DSB ends to block end resection in the G1 phase of the cell cycle. The restrictive action of the 53BP1 axis is alleviated by BRCA1-BARD1 in S and G2 phases via mechanisms that are poorly understood. Thus, BRCA1-deficient tumors, on account of their HDR-deficiency, are particularly vulnerable to PARP inhibitors (PARPi) due to synthetic lethality. However, dysfunction in the 53BP1 axis leads to HDR restoration and PARPi resistance.

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