A Kinase-Independent Role for the Rad3-Rad26 Complex in Recruitment of Tel1 to Telomeres in Fission Yeast

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ATM and ATR are two redundant checkpoint kinases essential for the stable maintenance of telomeres in eukaryotes. Previous studies have established that MRN (Mre11-Rad50-Nbs1) and ATRIP (ATR Interacting Protein) interact with ATM and ATR, respectively, and recruit their partner kinases to sites of DNA damage. Here, we investigated how Tel1^ATM and Rad3^ATR recruitment to telomeres is regulated in fission yeast. Quantitative chromatin immunoprecipitation (ChIP) assays unexpectedly revealed that the MRN complex could also contribute to the recruitment of Tel1^ATM to telomeres independently of the previously established Nbs1 C-terminal Tel1^ATM interaction domain. Recruitment of Tel1^ATM to telomeres in nbs1-c60Δ cells, which lack the C-terminal 60 amino acid Tel1^ATM interaction domain of Nbs1, was dependent on Rad3^ATR-Rad26^ATRIP, but the kinase domain of Rad3^ATR was dispensable. Thus, our results establish that the Rad3^ATR-Rad26^ATRIP complex contributes to the recruitment of Tel1^ATM independently of Rad3^ATR kinase activity, by a mechanism redundant with the Tel1^ATM interaction domain of Nbs1. Furthermore, we found that the N-terminus of Nbs1 contributes to the recruitment of Rad3^ATR-Rad26^ATRIP to telomeres. In response to replication stress, mammalian ATR–ATRIP also contributes to ATM activation by a mechanism that is dependent on the MRN complex but independent of the C-terminal ATM interaction domain of Nbs1. Since telomere protection and DNA damage response mechanisms are very well conserved between fission yeast and mammalian cells, mammalian ATR–ATRIP may also contribute to the recruitment of ATM to telomeres and to sites of DNA damage independently of ATR kinase activity.

Vyšlo v časopise: A Kinase-Independent Role for the Rad3-Rad26 Complex in Recruitment of Tel1 to Telomeres in Fission Yeast. PLoS Genet 6(2): e32767. doi:10.1371/journal.pgen.1000839
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1000839

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