Mammalian SWI/SNF chromatin remodeling complexes are required to prevent apoptosis after DNA damage.
Although SWI/SNF chromatin remodeling complexes play important roles in transcription, recent studies suggest that they also participate directly in DNA repair. In yeast, SWI/SNF and related RSC complexes have been shown to be recruited to the sites of DNA double strand breaks (DSBs) to facilitate DNA repair. We recently have shown that mammalian SWI/SNF complexes contribute to DBS repair by direct mechanisms of stimulating the phosphorylation of histone H2AX at DSB-surrounding chromatin. Here we investigated the role of mammalian SWI/SNF complexes in cell survival after DNA damage. When SWI/SNF was inactivated by means of dominant negativity or its catalytic subunit BRG1 was knockdowned by small interfering RNA, cells became highly susceptible to DNA damage-induced apoptosis. SWI/SNF inactivation had no effect on the activation and establishment of G2/M DNA damage checkpoint. However, SWI/SNF-defective cells could not sustain the G2/M checkpoint long enough to survive DNA damage, and rather underwent apoptosis before entering mitosis. We also found that, although the basal state and DNA damage-triggered activation of p53 were normal, the kinetics of p53 downregulation was significantly delayed in SWI/SNF-defective cells. Finally, the sustained p53 activation in SWI/SNF-defective cells was accompanied by accumulation of unrepaired DSBs owing to inefficient DNA repair. These results suggest that mammalian SWI/SNF complexes prevent DNA damage-induced apoptosis in part by facilitating efficient repair and thereby ensuring timely elimination of unrepaired DSBs that could otherwise lead to excessive prolongation of p53 activation.
Park
Ji-Hye
JH
Department of Life Science and Division of Life and Pharmaceutical Sciences, Ewha Womans University, Seoul, 120-750, Republic of Korea.
Park
Eun-Jung
EJ
Hur
Shin-Kyoung
SK
Kim
Sungsu
S
Kwon
Jongbum
J
D017209:Apoptosis; D018797:Cell Cycle Proteins / Q000378:metabolism; D016923:Cell Death; D002455:Cell Division; D002460:Cell Line; D002843:Chromatin / Q000378:metabolism*; D002868:Chromosomal Proteins, Non-Histone / Q000378:metabolism*; D053903:DNA Breaks, Double-Stranded; D004249:DNA Damage; D004260:DNA Repair; D016195:G2 Phase; D006801:Humans; D014157:Transcription Factors / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
D018797:Cell Cycle Proteins; D002843:Chromatin; D002868:Chromosomal Proteins, Non-Histone; C445179:SWI-SNF-B chromatin-remodeling complex; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53