# Regulation of DNA synthesis in response to DNA damage

> **NIH NIH R01** · COLUMBIA UNIVERSITY HEALTH SCIENCES · 2022 · $396,900

## Abstract

PROJECT SUMMARY
Genomic DNA is constantly challenged by DNA damage either spontaneously induced during cellular
metabolism or generated by exogenous DNA damaging agents. During DNA replication, DNA lesions can
cause the stalling or collapse of replication forks. Fork collapse results in the formation of DNA double-strand
breaks (DSBs). MCM8 and MCM9 (MCM8-9) form a helicase complex that promotes the repair of DSBs by
homologous recombination. We recently identified MCM8IP as a novel interactor of MCM8-9 that maintains
genomic integrity after replication stress. In particular, we showed that MCM8IP promotes DSB repair by
homologous recombination, facilitates the restart of replication forks arrested by DNA lesions and protects cells
from DNA damage generated by replication stress-inducing agents. Despite these important preliminary
findings, the precise mechanisms of action exhibited by MCM8IP, MCM8 and MCM9 during DNA
recombination and replication remain to be elucidated. MCM8 or MCM9 have been reported to act as tumor
suppressors and recent cancer genomic analyses have evidenced mutations in MCM8, MCM9 and MCM8IP in
multiple cancer types. The goals of this proposal are to define the precise biochemical and cellular activities
displayed by the MCM8IP-MCM8-9 complex for suppressing genomic instability and to examine how these
activities are affected by mutations in MCM8IP, MCM8 and MCM9 identified in tumors. In particular, we
propose 1) to define the biochemical activities and physical interactions exhibited by the MCM8IP-MCM8-9
complex for preserving genomic integrity; 2) to elucidate the mechanisms by which MCM8IP-MCM8-9
promotes DSB repair and ensures replication fork progression in response to DNA damage; 3) to evaluate the
contribution of MCM8IP, MCM8 and MCM9 cancer-associated mutations to genomic instability. Our approach
will utilize innovative proteomic methods, state-of-the-art genome editing technologies, single-molecule
analyses of replication dynamics, electron microscopy and super-resolution imaging. We anticipate that our
studies will define the unique mechanisms employed by the MCM8IP-MCM8-9 complex to suppress genomic
instability and will provide insights into the potential contribution of MCM8IP, MCM8 and MCM9 cancer-
associated mutations to cancer etiology.

## Key facts

- **NIH application ID:** 10320347
- **Project number:** 5R01CA197774-07
- **Recipient organization:** COLUMBIA UNIVERSITY HEALTH SCIENCES
- **Principal Investigator:** Alberto Ciccia
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $396,900
- **Award type:** 5
- **Project period:** 2015-12-01 → 2025-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10320347

## Citation

> US National Institutes of Health, RePORTER application 10320347, Regulation of DNA synthesis in response to DNA damage (5R01CA197774-07). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10320347. Licensed CC0.

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