Chromatin-remodeling factor, RSF1, controls p53-mediated transcription in apoptosis upon DNA strand breaks

摘要

Remodeling and spacing factor 1 (RSF1), which is one of chromatin-remodeling factors, has been linked to the DNA damage response (DDR) and DNA repair. However, the biological consequence of RSF1 deficiency in DDR in vivo and its molecular mechanisms remain unknown. Because defective DDR is related to neuropathological phenotypes, we developed neural-specific Rsf1 knockout mice. Rsf1 deficiency did not result in any neuropathological abnormalities, but prevented neural apoptosis triggered by excessive DNA strand breaks during neurogenesis. Likewise, cell death was significantly reduced in RSF1 deficient human cell lines after DNA damage, and the global transcriptome of these cells revealed that the expressions of p53 downstream genes were significantly reduced upon DNA strand breaks. Inactivation of these genes resulted from decreased binding of p53/p300 complex and subsequent reduction of H3 acetylation at their promoters. Our data show that RSF1 is necessary for p53-dependent gene expression in response to DNA strand breaks via controlling the accessibility of p53/p300 complex to its target genes and contributes to the maintenance of cellular integrity.