Research Paper Volume 9, Issue 12 pp 2529—2543
POT1 inhibits the efficiency but promotes the fidelity of nonhomologous end joining at non-telomeric DNA regions
- 1 Clinical and Translational Research Center of Shanghai First Maternity & Infant Hospital, Shanghai Key Laboratory of Signaling and Disease Research, School of Life Science and Technology, Tongji University, Shanghai 200092, China
- 2 State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, China
- 3 University of Pittsburgh Cancer Institute, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA
- 4 Center for Molecular Medicine, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China
Received: August 5, 2017 Accepted: December 1, 2017 Published: December 8, 2017
https://doi.org/10.18632/aging.101339How to Cite
Abstract
Robust DNA double strand break (DSB) repair and stabilized telomeres help maintain genome integrity, preventing the onset of aging or tumorigenesis. POT1 is one of the six factors in the shelterin complex, which protects telomeres from being recognized as DNA damages. TRF1 and TRF2, two other shelterin proteins, have been shown to participate in DNA DSB repair at non-telomeric regions, but whether POT1, which binds to single strand telomeric DNA at chromosomal ends, is involved in DNA DSB repair has not been assessed. Here we found that POT1 arrives at DNA damage sites upon the occurrence of DNA DSBs. It suppresses the efficiency of nonhomologous end joining (NHEJ), the major pathway for fixing DNA DSBs in mammals, but surprisingly promotes NHEJ fidelity. Mechanistic studies indicate that POT1 facilitates the recruitment of Artemis, which is a nuclease and promotes fidelity of NHEJ, to DNA damage sites. In addition, we found that overexpression of POT1 inhibits the protein stability of Lig3, which is the major regulator of alternative NHEJ (alt-NHEJ), therefore suppressing the efficiency of alt-NHEJ. Taken together we propose that POT1 is a key factor regulating the balance between the efficiency and fidelity of NHEJ at non-telomeric DNA regions.