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

Authors:
Alex W Klattenhoff
Alex W Klattenhoff
University of Pennsylvania
United States
Debolina Ray
Debolina Ray
Texas A&M University Health Science Center
Samy L Habib
Samy L Habib
University of Texas Health Science Center
United States
Dawit Kidane
Dawit Kidane
Yale University School of Medicine
United States

Oncotarget 2017 Dec 4;8(68):112942-112958. Epub 2017 Dec 4.

Division of Pharmacology and Toxicology, College of Pharmacy, The University of Texas at Austin, Dell Pediatric Research Institute, Austin, TX, United States.

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.

Download full-text PDF

Source
http://dx.doi.org/10.18632/oncotarget.22896DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5762564PMC
December 2017
3 Reads

Publication Analysis

Top Keywords

dna
9
atr inhibitor
8
neil3 dna
8
neil3-deficient cells
8
loss neil3
8
neil3
7
rpa contrast
4
contrast observed
4
observed marked
4
protein rpa
4
recruitment replication
4
replication protein
4
dsbs recruitment
4
marked decrease
4
nascent dna
4
replication fork
4
fork suggesting
4
suggesting hr-dependent
4
strands replication
4
dna strands
4

Similar Publications

Human NEIL3 is mainly a monofunctional DNA glycosylase removing spiroimindiohydantoin and guanidinohydantoin.

DNA Repair (Amst) 2013 Dec 5;12(12):1159-64. Epub 2013 Jun 5.

Department of Microbiology, University of Oslo, Oslo University Hospital, Rikshospitalet, PO Box 4950, Nydalen, NO-0424 Oslo, Norway.

Base excision repair is the major pathway for removal of oxidative DNA base damage. This pathway is initiated by DNA glycosylases, which recognize and excise damaged bases from DNA. In this work, we have purified the glycosylase domain (GD) of human DNA glycosylase NEIL3. Read More

View Article
December 2013

Human Nei-like protein NEIL3 has AP lyase activity specific for single-stranded DNA and confers oxidative stress resistance in Escherichia coli mutant.

Genes Cells 2009 Feb 15;14(2):261-70. Epub 2008 Jan 15.

Department of Molecular Genetics, Institute of Development, Aging and Cancer, Tohoku University, Aoba-ku, Sendai, Japan.

Oxidative base damage leads to alteration of genomic information and is implicated as a cause of aging and carcinogenesis. To combat oxidative damage to DNA, cells contain several DNA glycosylases including OGG1, NTH1 and the Nei-like proteins, NEIL1 and NEIL2. A third Nei-like protein, NEIL3, is composed of an amino-terminal Nei-like domain and an unknown carboxy-terminal domain. Read More

View Article
February 2009

DNA end resection is needed for the repair of complex lesions in G1-phase human cells.

Cell Cycle 2014 ;13(16):2509-16

a Department of Biophysics ; GSI Helmholtzzentrum für Schwerionenforschung GmbH ; Planckstraße 1; Darmstadt , Germany.

Repair of DNA double strand breaks (DSBs) is influenced by the chemical complexity of the lesion. Clustered lesions (complex DSBs) are generally considered more difficult to repair and responsible for early and late cellular effects after exposure to genotoxic agents. Resection is commonly used by the cells as part of the homologous recombination (HR) pathway in S- and G2-phase. Read More

View Article
August 2015

Loss of Neil3, the major DNA glycosylase activity for removal of hydantoins in single stranded DNA, reduces cellular proliferation and sensitizes cells to genotoxic stress.

Biochim Biophys Acta 2013 May 7;1833(5):1157-64. Epub 2013 Jan 7.

Department of Microbiology, University of Oslo, Oslo University Hospital, Rikshospitalet, Oslo, Norway.

7,8-Dihydro-8-oxoguanine (8-oxoG) is one of the most common oxidative base lesions in normal tissues induced by a variety of endogenous and exogenous agents. Hydantoins are products of 8-oxoG oxidation and as 8-oxoG, they have been shown to be mutagenic lesions. Oxidative DNA damage has been implicated in the etiology of various age-associated pathologies, such as cancer, cardiovascular diseases, arthritis, and several neurodegenerative diseases. Read More

View Article
May 2013