# Regulation of genome replication, recombination, and stress response

> **NIH NIH R35** · SLOAN-KETTERING INST CAN RESEARCH · 2024 · $708,000

## Abstract

Maintaining genome stability requires the intricate coordination of DNA replication, DNA repair, and the DNA
damage response. We have developed multi-disciplinary approaches to investigate some of the complex DNA
transactions and signaling in these processes that are poorly understood. Our areas of inquiry include the
regulation of the replisome and replication forks, the control of homologous recombination intermediates, and
dampening of the DNA damage response. Our findings have led to novel hypotheses and testing them will
deepen our understanding of critical genome regulation strategies.
 DNA replication must cope with many types of template barriers. The coping mechanisms entail close
collaboration between the replisome and many regulators. One of our long-term goals is to elucidate how
various regulators dynamically modify replisome functions. We will apply novel strategies to identify replisome
changes and determine how the highly conserved multi-functional Smc5/6 complex promotes replisome
function. Another goal of our studies is to determine the control of replication forks stalled at programmed
barriers within the ribosomal DNA. These sites suffer topological stress that can drive fork instability. We will
investigate how cells maintain the stalled replication forks in the face of this challenge to complete replication.
 When replication forks stalled by barriers fail to recover, collapsed forks and unreplicated DNA gaps can be
repaired by homologous recombination, generating repair intermediates such as Holliday junctions. Resolving
such joint DNA structures by specialized cleavage enzymes completes the repair process and prevents DNA
entanglement. These enzymes collaborate with a range of regulators to engender efficient repair; however, the
molecular roles of many regulators remain unclear. It is our goal to elucidate the mechanisms underlying the
roles of these regulators, including the functionally coupled Smc5/6 and Esc2. In addition. we will study
Smc5/6, which ties together DNA replication and recombinational control, in molecular detail.
 Genomic stress caused by DNA replication and repair failure activates the DNA damage checkpoint. While
activating this checkpoint is beneficial, its persistence is detrimental to growth. Dampening the DNA damage
checkpoint is thus essential to counter such harmful effects, but its mechanisms are understudied. One of our
research goals is to identify checkpoint dampening pathways and their licensing mechanisms. This line of
study will provide insights into the dynamic control of the DNA damage checkpoint.
 Outcomes of our proposed studies will expand our view of interconnected genome replication, repair, and
stress response processes and inform studies of diseases that are linked to the malfunction of these pathways.

## Key facts

- **NIH application ID:** 10928725
- **Project number:** 5R35GM145260-03
- **Recipient organization:** SLOAN-KETTERING INST CAN RESEARCH
- **Principal Investigator:** Xiaolan Zhao
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $708,000
- **Award type:** 5
- **Project period:** 2022-09-20 → 2027-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10928725

## Citation

> US National Institutes of Health, RePORTER application 10928725, Regulation of genome replication, recombination, and stress response (5R35GM145260-03). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10928725. Licensed CC0.

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