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

Publication date: 29 August 2017
Source:Cell Reports, Volume 20, Issue 9
Author(s): Jia Zhou, Jany Chan, Marie Lambelé, Timur Yusufzai, Jason Stumpff, Patricia L. Opresko, Markus Thali, Susan S. Wallace
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.

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Teaser

NEIL3 DNA glycosylase activity is critical in highly proliferating cells including cancer cells. Zhou et al. show that NEIL3 is specifically active at telomeres during S/G2, and that depletion of NEIL3 causes telomere dysfunction and thus mitotic defects, revealing its involvement in telomere repair, which prevents genome instability.


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