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XB-ART-53486
Nucleic Acids Res January 1, 2015; 43 (2): 875-92.
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DNA ligase III acts as a DNA strand break sensor in the cellular orchestration of DNA strand break repair.

Abdou I , Poirier GG , Hendzel MJ , Weinfeld M .


Abstract
In the current model of DNA SSBR, PARP1 is regarded as the sensor of single-strand breaks (SSBs). However, biochemical studies have implicated LIG3 as another possible SSB sensor. Using a laser micro-irradiation protocol that predominantly generates SSBs, we were able to demonstrate that PARP1 is dispensable for the accumulation of different single-strand break repair (SSBR) proteins at sites of DNA damage in live cells. Furthermore, we show in live cells for the first time that LIG3 plays a role in mediating the accumulation of the SSBR proteins XRCC1 and PNKP at sites of DNA damage. Importantly, the accumulation of LIG3 at sites of DNA damage did not require the BRCT domain-mediated interaction with XRCC1. We were able to show that the N-terminal ZnF domain of LIG3 plays a key role in the enzyme''s SSB sensing function. Finally, we provide cellular evidence that LIG3 and not PARP1 acts as the sensor for DNA damage caused by the topoisomerase I inhibitor, irinotecan. Our results support the existence of a second damage-sensing mechanism in SSBR involving the detection of nicks in the genome by LIG3.

PubMed ID: 25539916
PMC ID: PMC4333375
Article link: Nucleic Acids Res
Grant support: [+]

Species referenced: Xenopus
Genes referenced: lig3 mtor ogg1 parp1 pnkp ssb xrcc1


Article Images: [+] show captions
References [+] :
Caldecott, Protein ADP-ribosylation and the cellular response to DNA strand breaks. 2014, Pubmed