Post-translational modifications of histone proteins regulate numerous cellular processes. Among these modifications, trimethylation of lysine 36 in histone H3 (H3K36me3) and acetylation of lysine 16 in histone H4 (H4K16ac) have important roles in transcriptional regulation and DNA damage response signaling. However, whether these two epigenetic histone marks are mechanistically linked remains unclear. Here, we discovered a new pathway through which H3K36me3 stimulates H4K16ac upon DNA double-strand break (DSB) induction in human cells. In particular, we examined, using Western blot analysis, the levels of H3K36me3 and H4K16ac in cells after exposure to various DSB-inducing agents, including neocarzinostatin, γ rays and etoposide, and found that H3K36me3 and H4K16ac were both elevated in cells upon these treatments. We also observed that the DSB-induced H4K16 acetylation was abolished in cells upon depletion of the histone methyltransferase gene SET-domain containing 2 (SETD2) and the ensuing loss of H3K36me3. Furthermore, the H3K36me3-mediated increase in H4K16ac necessitated lens epithelium-derived growth factor p75 splicing variant (LEDGF), which is a reader protein of H3K36me3, and the KAT5 (TIP60) histone acetyltransferase. Mechanistically, the chromatin-bound LEDGF, through its interaction with KAT5, promoted chromatin localization of KAT5, thereby stimulating H4K16 acetylation. Together, we unveiled a crosstalk between two important histone epigenetic marks and defined the function of this crosstalk in DNA DSB repair.
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