Research Papers:
Loss of NEIL3 DNA glycosylase markedly increases replication associated double strand breaks and enhances sensitivity to ATR inhibitor in glioblastoma cells
PDF | HTML | Supplementary Files | How to cite
Metrics: PDF 1741 views | HTML 3381 views | ?
Abstract
Alex W. Klattenhoff1, Megha Thakur1, Christopher S. Chu1, Debolina Ray1, Samy L. Habib2 and Dawit Kidane1
1Division of Pharmacology and Toxicology, College of Pharmacy, The University of Texas at Austin, Dell Pediatric Research Institute, Austin, TX, United States
2South Texas Veterans Health System and Department of Cellular and Structural Biology, The University of Texas Health Science Center, San Antonio, TX, United States
Correspondence to:
Dawit Kidane, email: [email protected]
Keywords: DNA glycosylase; ATR; replication stress
Received: June 19, 2017 Accepted: November 16, 2017 Published: December 04, 2017
ABSTRACT
DNA endonuclease eight-like glycosylase 3 (NEIL3) is one of the DNA glycosylases that removes oxidized DNA base lesions from single-stranded DNA (ssDNA) and non-B DNA structures. Approximately seven percent of human tumors have an altered NEIL3 gene. However, the role of NEIL3 in replication-associated repair and its impact on modulating treatment response is not known. Here, we report that NEIL3 is localized at the DNA double-strand break (DSB) sites during oxidative DNA damage and replication stress. Loss of NEIL3 significantly increased spontaneous replication-associated DSBs and recruitment of replication protein A (RPA). In contrast, we observed a marked decrease in Rad51 on nascent DNA strands at the replication fork, suggesting that HR-dependent repair is compromised in NEIL3-deficient cells. Interestingly, NEIL3-deficient cells were sensitive to ataxia–telangiectasia and Rad3 related protein (ATR) inhibitor alone or in combination with PARP1 inhibitor. This study elucidates the mechanism by which NEIL3 is critical to overcome oxidative and replication-associated genotoxic stress. Our findings may have important clinical implications to utilize ATR and PARP1 inhibitors to enhance cytotoxicity in tumors that carry altered levels of NEIL3.
All site content, except where otherwise noted, is licensed under a Creative Commons Attribution 4.0 License.
PII: 22896