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
Affiliations
Jia Zhou
Department of Microbiology and Molecular Genetics, College of Medicine and College of Agriculture and Life Sciences, University of Vermont, Burlington, VT 05405, USA
Jany Chan
Department of Microbiology and Molecular Genetics, College of Medicine and College of Agriculture and Life Sciences, University of Vermont, Burlington, VT 05405, USA
Marie Lambelé
Department of Microbiology and Molecular Genetics, College of Medicine and College of Agriculture and Life Sciences, University of Vermont, Burlington, VT 05405, USA
Timur Yusufzai
Department of Radiation Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA
Jason Stumpff
Department of Molecular Physiology and Biophysics, College of Medicine, University of Vermont, Burlington, VT 05405, USA
Patricia L. Opresko
Department of Environmental and Occupational Health, University of Pittsburgh Graduate School of Public Health, Hillman Cancer Center, Pittsburgh, PA 15213, USA
Markus Thali
Department of Microbiology and Molecular Genetics, College of Medicine and College of Agriculture and Life Sciences, University of Vermont, Burlington, VT 05405, USA
Susan S. Wallace
Department of Microbiology and Molecular Genetics, College of Medicine and College of Agriculture and Life Sciences, University of Vermont, Burlington, VT 05405, USA
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.
