EEPD1 Promotes Repair of Oxidatively-stressed Replication Forks

Overview

Journal NAR Cancer

Publisher Oxford University Press

Specialty Oncology

Date 2023 Jan 23

PMID 36683914

Authors

Aruna S Jaiswal

Hyun-Suk Kim

Orlando D Scharer

Neelam Sharma

Elizabeth A Williamson

Gayathri Srinivasan

Linda Phillips

Kimi Kong

Shailee Arya

Anurag Misra

Arijit Dutta

Yogesh Gupta

Christi A Walter

Sandeep Burma

Satya Narayan

Patrick Sung

Jac A Nickoloff

Robert Hromas

Affiliations

Soon will be listed here.

Abstract

Unrepaired oxidatively-stressed replication forks can lead to chromosomal instability and neoplastic transformation or cell death. To meet these challenges cells have evolved a robust mechanism to repair oxidative genomic DNA damage through the base excision repair (BER) pathway, but less is known about repair of oxidative damage at replication forks. We found that depletion or genetic deletion of EEPD1 decreases clonogenic cell survival after oxidative DNA damage. We demonstrate that EEPD1 is recruited to replication forks stressed by oxidative damage induced by HO and that EEPD1 promotes replication fork repair and restart and decreases chromosomal abnormalities after such damage. EEPD1 binds to abasic DNA structures and promotes resolution of genomic abasic sites after oxidative stress. We further observed that restoration of expression of EEPD1 via expression vector transfection restores cell survival and suppresses chromosomal abnormalities induced by oxidative stress in EEPD1-depleted cells. Consistent with this, we found that EEPD1 preserves replication fork integrity by preventing oxidatively-stressed unrepaired fork fusion, thereby decreasing chromosome instability and mitotic abnormalities. Our results indicate a novel role for EEPD1 in replication fork preservation and maintenance of chromosomal stability during oxidative stress.

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