PPG Communications for Regulation of BRCA-dependent Genome Repair via the 53BP1 Axis Grant

Our Program Project focuses on elucidating the mechanistic underpinnings of homology-directed DNA repair (HDR) that is mediated by the tumor suppressors BRCA1-BARD1 and BRCA2 and how the 53BP1 regulatory axis restricts HDR to favor the engagement of non-homologous-DNA end joining as a DNA repair tool. We anticipate these endeavors to shed light on how DNA double-strand break repair pathway choice is regulated, help identify predictive biomarkers of cancer therapy response, and ultimately lead to the development of novel therapeutic strategies to treat breast, ovarian, and other cancers.

Project 1:
Role of DYNLL1 in the 53BP1 Axis of HDR Regulation

(Location: Dana-Farber Cancer Institute)

Narrative

DNA end resection has a key role in DSB repair and DNA replication. Any aberrations in DNA end resection can lead to genomic instability and also impact the therapeutic response to DNA-damaging drugs. Our discovery of DYNLL1, which interacts with MRE11 to inhibit end resection, provides a functional link between two distinct end resecting mechanisms, with one directly controlling MRE11 activity and the other indirectly regulating Shieldin-dependent end resection. Here, we will continue to shed light on how the functional interplay of the DNA end resection machinery and its regulatory circuitry impacts genome stability and sensitivity to PARPi.

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

(Location: UT Health San Antonio)

Narrative

DNA end resection is a critical step in the cellular response to DNA double-strand breaks (DSBs), which regulates repair pathway choice and promotes homology-directed repair (HDR). We propose to delineate novel mechanisms by which the opposing actions of 53BP1-CTC1-STN1-TEN1 (CST) and BRCA1-BARD1 regulate the activities of the long-range resection enzymes EXO1 and BLM-DNA2. Our findings will not only illuminate the mechanistic principles of DSB repair pathway choice but will also provide actionable information to help guide the development of targeted cancer therapies to treat HDR-deficient cancers and circumvent drug resistance.

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Project 3:
Antagonistic Mechanisms of BRCA2 and the 53BP1 Axis in RAD51 Nucleoprotein Filament Assembly

(Location: UT Health San Antonio)

Narrative

The proposal is focused on the mechanisms of control of DNA double-strand break repair by the CST and BRCA2-DSS1 complexes. Using biochemical, structural, and cell biology approaches, we will investigate the mechanisms of i) RAD51 restriction by CST, ii) reversal of this restriction by BRCA2-DSS1, and also iii) the role of the extended BRCA complex in the reversal of RAD51 restriction by CST. Our results will guide the development of novel therapeutics for breast, ovarian, and other cancers.

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