# Project 4: PARP-dependent Break Repair

> **NIH NIH P01** · UNIVERSITY OF CALIF-LAWRENC BERKELEY LAB · 2020 · $347,731

## Abstract

Project 4 – PARP-dependent break repair
PROJECT SUMMARY/ABSTRACT
The synthesis and turnover of poly(ADP-ribose) (PAR) in response to DNA damage plays an important role in
DNA damage repair. Notably, inhibitors of poly(ADP-ribose) polymerases (PARP) were developed to
selectively target cancer cells with defects in homologous recombination.In addition, PARP-dependent repair of
DNA single strand breaks (SSB)s is a major determinant in cell survival following exposure to genotoxic
antitumor agents such as temozolomide and camptothecin. Recently, PARP-dependent repair of DNA double
strand breaks (DSB)s by an alternative non-homologous end-joining (alt-NHEJ) pathway has been recently
identified as a novel therapeutic target in therapy-resistant forms of breast cancer and leukemia.
 Progress by investigators during SBDR-3 was the driving force for the development of this new project as
their research converged on a common theme of PARP-dependent responses to DNA damage. These efforts
were supported by the development of new protein expression strategies with the EMB core and new small
angle x-ray scattering approaches in the SCB core that have enabled us to gain insights into the size, shape
and flexibility of key proteins complexes involved in PARP-dependent DNA repair. To enhance this project, we
recruited a new investigator, Dr. Pascal, who has performed groundbreaking studies on the mechanism of
PARP activation by DNA damage using structural and biochemical approaches. In this project, we will utilize
the complementary strengths of our team in biophysics, biochemistry, structural and cell biology, and DNA
repair inhibitor development to gain insights at the molecular level into the regulation of DNA damage-
dependent PAR synthesis and turnover and the PARP-dependent repair of DNA strand-breaks.
 In Aim 1, we will focus on the interplay between PARP-1 and PARG that regulates DNA damage-
dependent PAR synthesis and degradation using structure-guided mutants that modulate the allosteric
activation of PARP-1 and inhibitors of PARG to determine how changing the levels of PAR synthesis and NAD+
depletion affects DNA repair and cell viability. In Aim 2, we will investigate how interactions between PARP-1
and XRCC1 complexes coordinate the repair of SSBs. In Aim 3, we will elucidate the mechanisms of PARP-
dependent repair of DSBs by alt-NHEJ, focusing on the interplay between XRCC1 and the
hMre11/hRad50/Nbs1 complex and the assembly of alt-NHEJ factors at DSBs in collaboration with project 5.
We envision that our studies will significantly advance understanding of the PARP-dependent responses to
DNA damage and will guide the development of more effective therapies for cancer.
 Our studies will continue to make extensive use of the EMB and SCB cores and are highly integrated with
the other four projects of SBDR-4. In particular, the role of PAR synthesis and turnover at the replication fork,
in other DNA repair pathways and in repair pathway choice will be ...

## Key facts

- **NIH application ID:** 10003202
- **Project number:** 5P01CA092584-20
- **Recipient organization:** UNIVERSITY OF CALIF-LAWRENC BERKELEY LAB
- **Principal Investigator:** Alan E Tomkinson
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $347,731
- **Award type:** 5
- **Project period:** 2001-09-27 → 2021-09-20

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10003202

## Citation

> US National Institutes of Health, RePORTER application 10003202, Project 4: PARP-dependent Break Repair (5P01CA092584-20). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10003202. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*