# Project 3: Homologous Recombinational Repair

> **NIH NIH P01** · UNIVERSITY OF CALIF-LAWRENC BERKELEY LAB · 2020 · $331,359

## Abstract

Project 3 – Homologous Recombination Repair
PROJECT SUMMARY/ABSTRACT
By eliminating DNA double-strand breaks (DSBs) and other deleterious chromosomal lesions, such as those
arising from replication fork (RF) stalling or collapse, homologous recombination-mediated DNA repair (HRR)
is critical for the maintenance of genome stability. In humans, several tumor suppressors, including BRCA2
and PALB2, function to ensure the successful completion of HRR. As such, mutations in these proteins and
their partners cause hypersensitivity to agents that damage DNA or replication forks and can lead to cancer
formation.
 During the HRR process, a primary lesion is resected nucleolytically to yield ssDNA, which becomes
occupied by the abundant single-stranded DNA binding protein RPA. For HRR to occur, RPA must be replaced
by the RAD51 recombinase enzyme, which catalyzes the search for a DNA homolog to initiate the HRR
reaction. RAD51 functions within the context of a filamentous intermediate on ssDNA, commonly referred to as
the presynaptic filament. The handoff from RPA to RAD51 in presynaptic filament assembly is facilitated by
HRR factors known as “mediators”. We will capitalize on major advances made during SBDR-3 to dissect the
mechanistic roles of the human HRR mediators. A combination of biochemical, biophysical, genetic, and cell-
based approaches will be employed in four specific aims to define the action of the XPG-PALB2-BRCA2-DSS1
complex and of several conserved RAD51 paralogs in the assembly of the presynaptic filament. We will (1)
decipher the presynaptic functions of BRCA2-DSS1 and PALB2, (2) determine the molecular mechanism of
the role of XPG, (3) elucidate the structural biochemistry of the RAD51 paralogs, and (4) analyze the promotion
of presynaptic filament assembly by these mediators at the single-molecule level. The results from our
endeavors will allow us to formulate detailed models to elucidate HRR mechanisms in human cells. Given the
importance of HRR in tumor suppression, our work has direct, strong relevance to cancer biology, and has the
potential to identify strategies and targets for therapeutic intervention in cancer treatment. The success of our
project studies and of the entire SBDR program is assured by the synergistic research structure that we have
established and the exceptional services provided by the two research cores.

## Key facts

- **NIH application ID:** 10003200
- **Project number:** 5P01CA092584-20
- **Recipient organization:** UNIVERSITY OF CALIF-LAWRENC BERKELEY LAB
- **Principal Investigator:** Patrick Sung
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $331,359
- **Award type:** 5
- **Project period:** 2001-09-27 → 2021-09-20

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10003200

## Citation

> US National Institutes of Health, RePORTER application 10003200, Project 3: Homologous Recombinational Repair (5P01CA092584-20). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10003200. Licensed CC0.

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