NEIL3 Repairs Telomere Damage during S Phase to Secure Chromosome Segregation at Mitosis

Jia Zhou; Jany Chan; Marie Lambelé; Timur Yusufzai; Jason Stumpff; Patricia L Opresko; Markus Thali; Susan S Wallace

doi:10.1016/j.celrep.2017.08.020

NEIL3 Repairs Telomere Damage during S Phase to Secure Chromosome Segregation at Mitosis

Cell Rep. 2017 Aug 29;20(9):2044-2056. doi: 10.1016/j.celrep.2017.08.020.

Authors

Jia Zhou¹, Jany Chan², Marie Lambelé², Timur Yusufzai³, Jason Stumpff⁴, Patricia L Opresko⁵, Markus Thali⁶, Susan S Wallace⁷

Affiliations

¹ Department of Microbiology and Molecular Genetics, College of Medicine and College of Agriculture and Life Sciences, University of Vermont, Burlington, VT 05405, USA; Graduate Program in Cell and Molecular Biology, University of Vermont, Burlington, VT 05405, USA; Department of Radiation Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA; Department of Biological Chemistry & Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA.
² Department of Microbiology and Molecular Genetics, College of Medicine and College of Agriculture and Life Sciences, University of Vermont, Burlington, VT 05405, USA.
³ Department of Radiation Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA; Department of Biological Chemistry & Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA.
⁴ Department of Molecular Physiology and Biophysics, College of Medicine, University of Vermont, Burlington, VT 05405, USA; Graduate Program in Cell and Molecular Biology, University of Vermont, Burlington, VT 05405, USA.
⁵ Department of Environmental and Occupational Health, University of Pittsburgh Graduate School of Public Health, Hillman Cancer Center, Pittsburgh, PA 15213, USA.
⁶ Department of Microbiology and Molecular Genetics, College of Medicine and College of Agriculture and Life Sciences, University of Vermont, Burlington, VT 05405, USA; Graduate Program in Cell and Molecular Biology, University of Vermont, Burlington, VT 05405, USA. Electronic address: markus.thali@uvm.edu.
⁷ Department of Microbiology and Molecular Genetics, College of Medicine and College of Agriculture and Life Sciences, University of Vermont, Burlington, VT 05405, USA; Graduate Program in Cell and Molecular Biology, University of Vermont, Burlington, VT 05405, USA. Electronic address: susan.wallace@uvm.edu.

Abstract

Oxidative damage to telomere DNA compromises telomere integrity. We recently reported that the DNA glycosylase NEIL3 preferentially repairs oxidative lesions in telomere sequences in vitro. Here, we show that loss of NEIL3 causes anaphase DNA bridging because of telomere dysfunction. NEIL3 expression increases during S phase and reaches maximal levels in late S/G2. NEIL3 co-localizes with TRF2 and associates with telomeres during S phase, and this association increases upon oxidative stress. Mechanistic studies reveal that NEIL3 binds to single-stranded DNA via its intrinsically disordered C terminus in a telomere-sequence-independent manner. Moreover, NEIL3 is recruited to telomeres through its interaction with TRF1, and this interaction enhances the enzymatic activity of purified NEIL3. Finally, we show that NEIL3 interacts with AP Endonuclease 1 (APE1) and the long-patch base excision repair proteins PCNA and FEN1. Taken together, we propose that NEIL3 protects genome stability through targeted repair of oxidative damage in telomeres during S/G2 phase.

Keywords: DNA repair; NEIL3 glycosylase; mitotic defects; telomere.

MeSH terms

CD4-Positive T-Lymphocytes / metabolism
Cell Cycle Checkpoints
Cell Nucleus / metabolism
Chromosome Segregation*
DNA / metabolism
DNA Damage*
DNA Repair*
Gene Knockdown Techniques
HCT116 Cells
HeLa Cells
Humans
Microtubules / metabolism
Mitosis*
N-Glycosyl Hydrolases / chemistry
N-Glycosyl Hydrolases / metabolism*
Oxidative Stress
Protein Binding
Protein Domains
S Phase*
Spindle Apparatus / metabolism
Telomere / pathology*

Substances

DNA
N-Glycosyl Hydrolases
NEIL3 protein, human

Abstract

MeSH terms

Substances

Grants and funding