A HDAC4-HDAC2 complex composes an epigenetic sensor that links the DNA damage response to the senescent program by erasing H2BK120 acetylation [II]

Purpose: Identification of SEs in time course after HDAC4 depletion and correlation to the accumulation of DNA damage. Outcome: We discovered a novel epigenetic complex formed by HDAC4 and HDAC2 that is involved in the erasure of H2BK120 acetylation. The HDAC4/HDAC2 complex, through the dynamic deacetylation of H2BK120, modulates the efficiency of DNA repair by homologous recombination (HR) by controlling the recruitment of BRCA1 and CtIP to the site of lesions. Degradation of HDAC4 during senescence has a dual effect. First, it contributes to super-enhancers activation by limiting HDAC3 activity, and second, it causes the accumulation of damaged DNA. Identification of SEs (H3K27ac and H3K4me1 co-presence) in SK-LMS-1 Leiomyosarcomas cells deleted for HDAC4 using CRISPR/Cas9 and re-expressing a tamoxifen-inducible PAM mutant version of HDAC4 (HDAC4-/-/HDAC4-/-PAM-ER) at 0, 12 and 36h from HDAC4 depletion.