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TIP60 acetylates H2AZ and regulates doxorubicin-induced DNA damage sensitivity through RAD51 transcription

Lee, K. K.; Zhang, Y.; Magallanes, R. T.; Rajagopalan, D.; Bhatia, S. S.; Ng, L.; Desi, N.; Tham, C. Y.; Teo, W. S.; Hoppe, M. M.; Jeyasekharan, A.; Tay, Y.; Chng, W. J.; Tenen, D. G.; Benoukraf, T.; Jha, S.

2020-06-12 molecular biology
10.1101/2020.06.10.145193 bioRxiv
Show abstract

TIP60, a lysine acetyltransferase and H2AZ, a histone H2A variant are involved in transcription and DNA repair. Recent studies suggest that H2AZ acetylation is dependent on TIP60. Here, we show that TIP60 acetylates both isoforms of H2AZ in vitro and in cells. Utilizing ChIP-seq and RNA-seq to identify the genes regulated by TIP60-dependent acetylation of H2AZ, we find that TIP60-dependent acetylation of H2AZ correlates with the expression of genes involved in DNA damage repair, amongst several other pathways. In line with this, TIP60-depleted cells exhibit increased sensitivity to the DNA damage-inducing drug doxorubicin. Restoring the expression level of RAD51, one of the genes involved in the DNA damage repair pathway, partially rescues the doxorubicin sensitivity due to TIP60 depletion. Overall, our study uncovers a role for TIP60 in regulating doxorubicin-induced DNA damage sensitivity in a manner dependent on RAD51 transcription.

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