The chromatin remodeling protein INO80 contributes to the removal of H2A.Z at the p53‐binding site of the p21 gene in response to doxorubicin

Abstract

Transcriptional activation of p21 (cyclin-dependent kinase inhibitor 1A) due to DNA damage often alters the distribution of histone variant H2A.Z at the p21 gene. However, whether the human INO80 complex regulates changes in H2A.Z at the p21 promoter is unclear. We show here that activation of p21 expression by doxorubicin (Doxo) in U2OS cells is required for removal of H2A.Z by INO80 at the p53-binding site proximal region (-2.2 kb) of the p21 promoter. A purified INO80 complex, but not the INO80E653Q mutant-complex, which lost DNA-sliding activity, is mainly responsible for removing H2A.Z from reconstituted nucleosomes in vitro. This activity was enhanced with MOF-mediated histone acetylation, suggesting that INO80 more readily removes H2A.Z from loosened nucleosomes. Also, co-occupancy of INO80 and H2A.Z -2.2 kb upstream of the p21 transcriptional start site (TSS) was observed. H2A.Z at this region was removed in a short time after Doxo treatment and activated p21 expression. However, p21 induction was inhibited by INO80 knockdown by delaying H2A.Z removal, indicating the need for INO80. Moreover, shMOF-mediated histone acetylation reduced recruitment of INO80 -2.2 kb upstream of p21 TSS and inhibited the removal of H2A.Z in Doxo-treated cells. These data provide new insights into the transcriptional regulation of p21 by the INO80 complex.

A yeast phenomic model for the influence of Warburg metabolism on genetic buffering of doxorubicin

“…10B ), the latter explained by its role of histone acetylation in recruitment of DNA repair machinery to dsDNA break sites [52]. The Ino80 complex influences doxorubicin response in fission yeast [141, 142], further suggesting evolutionary conservation of this interaction, and thus potential relevance to mammalian systems [143]. DNA repair pathways, such as those involving RAD52 and INO80 , are evolutionarily conserved, involved in genome instability and tumorigenesis [144], and predictive of therapeutic response in some cancers [145], thus representing potential tumor-specific biomarkers for chemotherapeutic efficacy.…”

Mutational Damages in Malignant Lung Tumors

“…Recent studies by several authors (Ding, 2018;Sui, 2019;Meliala, 2020; showed that the transactivation of p21 (cyclin-dependent kinase inhibitor 1A) is closely related to the recruitment of transcription cofactors at the p53 responsive elements (p53REs) in its promoter region. Human chromatin remodeling enzyme INO80 can be recruited to the p53REs of the p21 promoter and negatively regulates p21 (Ding, 2018).…”

YY1/BCCIP Coordinately Regulates P53-Responsive Element (p53RE)-Mediated Transactivation of p21Waf1/Cip1

“…Our data, combined with previously reported data, have confirmed that YY1 can be recruited at the p53 binding site in the p21 promoter and be involved in the regulation of p21 transcription [9,13], suggesting that the recruitment of INO80 complex to the p53 binding site of the p21 TSS may be achieved by YY1. Based on the most recent report, the recruitment of INO80 complex to the p53 binding site in the p21 promoter may function in two different ways according to the intracellular condition: i) the INO80 complex represses p21 expression by regulating the promoter proximal nucleosome arrangement under normal cellular conditions; ii) in Doxo-treated cells, the INO80 complex rapidly removes accumulated H2A.Z and relieves its inhibition of p21 , thereby inducing the transcriptional expression of p21 [27].…”