POT1 inhibits the efficiency but promotes the fidelity of nonhomologous end joining at non-telomeric DNA regions

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.

Back to the future: The intimate and evolving connection between telomere-related factors and genotoxic stress

“…3). The association of POT1 with the telomeric G-overhang prevents activation of an ATR-mediated DNA damage response (61), and recent studies indicate that human POT1 increases the fidelity of NHEJ at nontelomeric sites (62). Intriguingly, the C terminus of hPOT1 bears structural similarity to a Holliday junction resolvase domain (63), supporting the notion that POT1 affects other facets of DNA metabolism beyond telomere biology.…”

Rac GTPase activating protein 1 promotes gallbladder cancer via binding DNA ligase 3 to reduce apoptosis

“…Our study also demonstrated that RACGAP1 regulates LIG3 stability. Yang Yu et al indicated that POT1 promotes LIG3 proteasomal degradation through DDR-associated kinase activation 42 . LIG3 functions as a PARP1-binding nuclear protein that is also subjected to PARylation by PARP1.…”

<p>Shelterin Complex at Telomeres: Implications in Ageing</p>

“…51,54 It has been shown that TRF1 and TRF2 participate in DNA double-strand break repair at non-telomeric regions. 58 Both TRF1 and TRF2 regulate telomerase activity, but neither plays a role in regulating telomerase gene expression. 59 TRF1 suppresses telomerase action on telomere region, while TRF2 activates a telomeric degradation without any effect on telomerase.…”

“…103 Yu et al demonstrated that at the time of DNA double-strand breaks, POT1 arrives at DNA damage sites. 58 It suppresses the efficiency of non-homologous endjoining (NHEJ), fixes DNA double-strand breaks, and promotes NHEJ fidelity. 58 Also, POT1 overexpression represses the protein stability of Lig3, which is the principal regulator of alternative NHEJ (alt-NHEJ), hence inhibits the efficiency of alt-NHEJ.…”

“…58 Also, POT1 overexpression represses the protein stability of Lig3, which is the principal regulator of alternative NHEJ (alt-NHEJ), hence inhibits the efficiency of alt-NHEJ. 58…”