EEPD1 promotes repair of oxidatively-stressed replication forks

Author:

Jaiswal Aruna S1,Kim Hyun-Suk2,Schärer Orlando D23,Sharma Neelam4,Williamson Elizabeth A1,Srinivasan Gayathri1,Phillips Linda1,Kong Kimi1,Arya Shailee5,Misra Anurag5,Dutta Arijit5,Gupta Yogesh5ORCID,Walter Christi A6,Burma Sandeep57,Narayan Satya8,Sung Patrick5,Nickoloff Jac A4ORCID,Hromas Robert1ORCID

Affiliation:

1. Division of Hematology and Medical Oncology, Department of Medicine and the Mays Cancer Center, University of Texas Health Science Center , San Antonio , TX 78229, USA

2. Center for Genomic Integrity, Institute for Basic Science , Ulsan , Republic of Korea

3. Department of Biological Sciences, School of Life Sciences, Ulsan National Institute of Science and Technology , Ulsan , Republic of Korea

4. Department of Environmental and Radiological Health Sciences, Colorado State University , Fort Collins , CO 80523, USA

5. Department of Biochemistry and Structural Biology, University of Texas Health Science Center , San Antonio , TX 78229, USA

6. Department of Cell Systems and Anatomy, University of Texas Health Science Center , San Antonio , TX 78229, USA

7. Department of Neurosurgery, University of Texas Health Science Center , San Antonio , TX 78229, USA

8. Department of Anatomy and Cell Biology, University of Florida , Gainesville , FL 32610, USA

Abstract

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 H2O2 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.

Funder

National Institutes of Health

Cancer Prevention and Research Institute of Texas

American Lung Association

NIH

Max and Minnie Tomerlin Voelcker Foundation and NIH

Publisher

Oxford University Press (OUP)

Subject

General Medicine

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