# Roles of Chromatin Modification in BRCA1 Dependent DNA Repair

> **NIH NIH R01** · UNIVERSITY OF PENNSYLVANIA · 2021 · $382,375

## Abstract

Contact PD/PI: Greenberg, Roger A.
Summary
DNA repair execution is among the most important determinants of cancer etiology and response to therapy;
mandating intimate knowledge of its molecular mechanisms and the vulnerabilities that present when it is altered.
Cancer cells frequently harbor changes in their relative utilization (rewiring) of competing DNA repair
mechanisms, and this has a profound influence on cancer genome evolution and clinical response to targeted
agents. Prominent examples reside in hereditary breast and ovarian cancer syndrome and in a different spectrum
of cancers that maintain telomere length through homologous recombination. Germline BRCA1 and BRCA2
gene mutations confer high penetrance breast and ovarian cancer. Both proteins are required for canonical,
Rad51 dependent homologous recombination, thus accounting for the increased sensitivity to poly(ADP)ribose
polymerase inhibitors (PARPi) exhibited by BRCA null tumors. Unfortunately, less than half of BRCA mutant
cancers initially respond to PARPi and resistance invariably emerges in those that do. How DNA repair occurs
in the context of BRCA dysfunction is therefore a question of central importance. Some clues exist as to the
factors that influence this process. Namely, compelling genetic evidence indicates that hyperactivation of specific
chromatin directed DNA repair mechanisms strongly influences genome integrity, cancer etiology, and response
to therapy in BRCA mutant cells. To understand the biochemical basis for this phenomenon, my laboratory has
developed approaches to identify the full spectrum of combinatorial nucleosome modifications that mediate
recognition of damaged chromatin and directs utilization of specific DNA repair mechanisms. Notably, chromatin
alterations also underlie the poorly understood phenomenon of alternative telomere lengthening (ALT), an
evolutionarily conserved form of telomere maintenance that occurs in nearly 15% of human cancers. We have
recently shown that ALT relies on BRCA-Rad51 independent homologous recombination and enacts dramatic
changes in higher order chromatin structure to synthesize long telomere tracts in response to double-stranded
DNA breaks. This was made possible by our development of methodologies to synchronously activate ALT and
visualize every major step encompassing homologous recombination in real time at ALT telomeres. Interestingly,
we observe overlapping genetic vulnerabilities in ALT and BRCA mutant cells, suggesting commonality in the
repair processes that ensue in each scenario. Our overarching goals are to delineate molecular events
necessary for canonical and alternative mechanisms of homologous recombination that arises in the setting of
(1) therapeutic resistance in BRCA mutant cells, and (2) during ALT. These objectives will be performed in
parallel and with equal emphasis. Our studies will yield fundamental advances to the understanding cancer
genome integrity control and clarify new strategies to ta...

## Key facts

- **NIH application ID:** 10061558
- **Project number:** 5R01CA174904-08
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** Roger A Greenberg
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $382,375
- **Award type:** 5
- **Project period:** 2013-04-01 → 2023-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10061558

## Citation

> US National Institutes of Health, RePORTER application 10061558, Roles of Chromatin Modification in BRCA1 Dependent DNA Repair (5R01CA174904-08). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10061558. Licensed CC0.

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