Loss of NEIL3 DNA glycosylase markedly increases replication associated double strand breaks and enhances sensitivity to ATR inhibitor in glioblastoma cells

Alex W. Klattenhoff, Megha Thakur, Christopher S. Chu, Debolina Ray, Samy L. Habib, Dawit Kidane

Research output: Contribution to journalArticle

4 Citations (Scopus)

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 HRdependent 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.

Original languageEnglish (US)
Pages (from-to)112942-112958
Number of pages17
JournalOncotarget
Volume8
Issue number68
DOIs
StatePublished - Jan 1 2017

Fingerprint

DNA Glycosylases
Glioblastoma
DNA Damage
DNA
Replication Protein A
Ataxia Telangiectasia
Double-Stranded DNA Breaks
Single-Stranded DNA
Deoxyribonuclease I
DNA Replication
Neoplasms
Genes
Proteins

Keywords

  • ATR
  • DNA glycosylase
  • Replication stress

ASJC Scopus subject areas

  • Oncology

Cite this

Loss of NEIL3 DNA glycosylase markedly increases replication associated double strand breaks and enhances sensitivity to ATR inhibitor in glioblastoma cells. / Klattenhoff, Alex W.; Thakur, Megha; Chu, Christopher S.; Ray, Debolina; Habib, Samy L.; Kidane, Dawit.

In: Oncotarget, Vol. 8, No. 68, 01.01.2017, p. 112942-112958.

Research output: Contribution to journalArticle

Klattenhoff, Alex W. ; Thakur, Megha ; Chu, Christopher S. ; Ray, Debolina ; Habib, Samy L. ; Kidane, Dawit. / Loss of NEIL3 DNA glycosylase markedly increases replication associated double strand breaks and enhances sensitivity to ATR inhibitor in glioblastoma cells. In: Oncotarget. 2017 ; Vol. 8, No. 68. pp. 112942-112958.
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