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Mdc1 couples DNA double-strand break recognition by Nbs1 with its H2AX-dependent chromatin retention
C Lukas, F Melander, M Stucki, J Falck, S Bekker-Jensen, M Goldberg, Y Lerenthal, SP Jackson, J Bartek, J Lukas
Jazyk angličtina Země Anglie, Velká Británie
PubMed Central od 1982 do Před 1 rokem
Europe PubMed Central od 1982 do Před 1 rokem
ProQuest Central od 2000-01-04 do 2013-12-11
Open Access Digital Library od 1997-01-01
Open Access Digital Library od 1997-01-01
Medline Complete (EBSCOhost) od 1997-01-02 do Před 1 rokem
Health & Medicine (ProQuest) od 2000-01-04 do 2013-12-11
Public Health Database (ProQuest) od 2000-01-04 do 2013-12-11
Odkazy
PubMed
15201865
Knihovny.cz E-zdroje
- MeSH
- buněčné jádro metabolismus MeSH
- chromatin * metabolismus MeSH
- DNA vazebné proteiny * metabolismus MeSH
- fluorescenční barviva MeSH
- fluorescenční protilátková technika MeSH
- fosfoproteiny metabolismus MeSH
- histony * metabolismus MeSH
- hydraziny MeSH
- jaderné proteiny chemie metabolismus MeSH
- konfokální mikroskopie MeSH
- lidé MeSH
- malá interferující RNA metabolismus MeSH
- monoklonální protilátky MeSH
- nádorové buněčné linie MeSH
- osteosarkom patologie MeSH
- poškození DNA * MeSH
- proteiny buněčného cyklu chemie metabolismus MeSH
- RNA interference MeSH
- terciární struktura proteinů MeSH
- trans-aktivátory * MeSH
- Check Tag
- lidé MeSH
Mdc1/NFBD1 controls cellular responses to DNA damage, in part via interacting with the Mre11-Rad50-Nbs1 complex that is involved in the recognition, signalling, and repair of DNA double-strand breaks (DSBs). Here, we show that in live human cells, the transient interaction of Nbs1 with DSBs and its phosphorylation by ATM are Mdc1-independent. However, ablation of Mdc1 by siRNA or mutation of the Nbs1's FHA domain required for Mdc1 binding reduced the affinity of Nbs1 for DSB-flanking chromatin and caused aberrant pan-nuclear dispersal of Nbs1. This occurred despite normal phosphorylation of H2AX, indicating that lack of Mdc1 does not impair this DSB-induced chromatin change, but rather precludes the sustained engagement of Nbs1 with these regions. Mdc1 (but not Nbs1) became partially immobilized to chromatin after DSB generation, and siRNA-mediated depletion of H2AX prevented such relocalization of Mdc1 and uncoupled Nbs1 from DSB-flanking chromatin. Our data suggest that Mdc1 functions as an H2AX-dependent interaction platform enabling a switch from transient, Mdc1-independent recruitment of Nbs1 to DSBs towards sustained, Mdc1-dependent interactions with the surrounding chromosomal microenvironment.
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