Title | Recruitment and activation of the ATM kinase in the absence of DNA-damage sensors. |
Publication Type | Journal Article |
Year of Publication | 2015 |
Authors | Hartlerode AJ, Morgan MJ, Wu Y, Buis J, Ferguson DO |
Journal | Nat Struct Mol Biol |
Volume | 22 |
Issue | 9 |
Pagination | 736-43 |
Date Published | 2015 Sep |
ISSN | 1545-9985 |
Keywords | Animals, Ataxia Telangiectasia Mutated Proteins, DNA, DNA Breaks, Double-Stranded, Mice, Protein Binding |
Abstract | Two kinases, ATM and DNA-PKcs, control rapid responses to DNA double-strand breaks (DSBs). The paradigm for ATM control is recruitment and activation by the Mre11-Rad50-NBS1 (MRN) sensor complex, whereas DNA-PKcs requires the sensor Ku (Ku70-Ku80). Using mouse cells containing targeted mutant alleles of Mre11 (Mre11a) and/or Ku70 (Xrcc6), together with pharmacologic kinase inhibition, we demonstrate that ATM can be activated by DSBs in the absence of MRN. When MRN is deficient, DNA-PKcs efficiently substitutes for ATM in facilitating local chromatin responses. In the absence of both MRN and Ku, ATM is recruited to chromatin, where it phosphorylates H2AX and triggers the G2-M cell-cycle checkpoint, but the DNA-repair functions of MRN are not restored. These results suggest that, in contrast to straightforward recruitment and activation by MRN, a complex interplay between sensors has a substantial role in ATM control. |
DOI | 10.1038/nsmb.3072 |
Alternate Journal | Nat. Struct. Mol. Biol. |
PubMed ID | 26280532 |
PubMed Central ID | PMC4560612 |
Grant List | 5-P30-CA46592 / CA / NCI NIH HHS / United States P30 CA046592 / CA / NCI NIH HHS / United States R01-HL079118 / HL / NHLBI NIH HHS / United States R01 HL079118 / HL / NHLBI NIH HHS / United States T32 CA009676 / CA / NCI NIH HHS / United States T32CA009676 / CA / NCI NIH HHS / United States T32 AI007413 / AI / NIAID NIH HHS / United States |
Submitted by kej2006 on June 6, 2018 - 4:11pm