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

Abstract

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.

The Anti-Cancer Effect of Mangifera indica L. Peel Extract is Associated to γH2AX-mediated Apoptosis in Colon Cancer Cells

“…Importantly, the DNA damage effect in treated Caco-2 and HCT116 cells was also accompanied by an increase in p53 level, the genome guardian protein capable of orchestrating a variety of DNA damage responses (DDR) and inducing apoptotic cell death [41]. In contrast, such an effect was not observed in HT29 cells, which are known to express a mutated form of this protein [42,43,44].…”

Tumor suppressor p53: from engaging DNA to target gene regulation

“…This includes key modulators of histone modification state, such as CBP and p300 (mediating H3K27ac) ( 101 , 102 ), TIP60 and hMOF (H4K16ac) ( 103 , 104 ), GCN5/PCAF (H3K9ac) ( 105 ), and the H3K27me3 demethylase KDM6B ( 54 ). p53 can also directly interact with components of chromatin remodeling complexes, such as RSF1 ( 106 ), BRG1 ( 107 ), ARID1A ( 108 ), BRD7 ( 55 ), and TRRAP ( 109 ). These interactions are not limited to those supporting p53-dependent trans -activation, as p53 also associates with known transcriptional repressors, such as histone deacetylases (HDACs) ( 110 ) as well as modulators of repressive chromatin and heterochromatin including PCL1 ( 111 ), KMT5A/SETD8 ( 112 ), LSD1 ( 113 ), SMYD2 ( 114 ), SUV39H1 ( 115 ), USP7 ( 116 ), as well as EHMT1 and EHMT2 ( 117 ).…”

Regulation of Adult Neurogenesis in Mammalian Brain

“…The family of transcriptional factors p53, p63 and p73 [ 96 , 97 , 98 , 99 , 100 , 101 , 102 ] are well known and characterised for their role in the control of the cell cycle arrest and apoptosis [ 103 , 104 , 105 , 106 , 107 , 108 , 109 , 110 , 111 ]. Together with the frequent p53 mutations in cancer [ 112 , 113 , 114 , 115 , 116 , 117 , 118 , 119 , 120 , 121 , 122 ], this signalling leads to associate their function to oncosuppression [ 123 , 124 , 125 , 126 ].…”