Open AccessDefective ATM ‐Kap‐1‐mediated chromatin remodeling impairs DNA repair and accelerates senescence in progeria mouse model
Author(s) -
Liu Baohua,
Wang Zimei,
Ghosh Shrestha,
Zhou Zhongjun
Publication year - 2013
Publication title -
aging cell
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.103
H-Index - 140
eISSN - 1474-9726
pISSN - 1474-9718
DOI - 10.1111/acel.12035
Subject(s) - progeria , chromatin , biology , chromatin remodeling , dna damage , microbiology and biotechnology , senescence , dna repair , premature aging , dna , cancer research , genetics , gene
Summary ATM ‐mediated phosphorylation of KAP ‐1 triggers chromatin remodeling and facilitates the loading and retention of repair proteins at DNA lesions. Mouse embryonic fibroblasts ( MEF s) derived from Zmpste24 −/− mice undergo early senescence, attributable to delayed recruitment of DNA repair proteins. Here, we show that ATM ‐Kap‐1 signaling is compromised in Zmpste24 −/− MEF s, leading to defective DNA damage‐induced chromatin remodeling. Knocking down Kap‐1 rescues impaired chromatin remodeling, defective DNA repair and early senescence in Zmpste24 −/− MEF s. Thus, ATM ‐Kap‐1‐mediated chromatin remodeling plays a critical role in premature aging, carrying significant implications for progeria therapy.