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.
Highlights
Genomic stability is constantly threatened by DNA damages arising from a variety of endogenous and exogenous sources
To test the hypothesis that POT1 participates in DNA double strand break (DSB) repair, we first examined if POT1 is recruited to DNA DSB sites using microirradiation
To confirm POT1 arrives at DNA DSB sites, we performed ChIP assay using our well-established nonhomologous end joining (NHEJ)-I9a cell line with one copy of NHEJ reporter integrated into genomes [6]
Summary
Genomic stability is constantly threatened by DNA damages arising from a variety of endogenous and exogenous sources. Among all types of DNA damages, DNA double strand breaks (DSBs) are the most harmful as unrepaired or inappropriately repaired DSBs may introduce deletions, insertions or chromosomal rearrangements to genomes, leading to severe consequences including the onset of aging and tumorigenesis. Precisely repairing DNA DSBs is critical to stabilizing genomes. The molecular mechanisms of alt-NHEJ www.aging‐us.com pathway have not been well studied, but several factors including PARP1 and DNA Lig have been documented to be involved in the repair process [5]. Much knowledge has been learned on the regulatory mechanisms of DNA DSB repair by NHEJ [9,10,11,12], but most of the studies have been on how the efficiency of NHEJ is determined by various factors. And intriguingly, the regulation of NHEJ fidelity has only received little attention
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