Histone deacetylation regulates nucleotide excision repair through an interaction with the XPC protein

The XPC protein complex plays a central role in DNA lesion recognition for global genome nucleotide excision repair (GG-NER). Lesion recognition can be accomplished in either a UV-DDB-dependent or -independent manner; however, it is unclear how these sub-pathways are regulated in chromatin. Here, we show that histone deacetylases 1 and 2 facilitate UV-DDB-independent recruitment of XPC to DNA damage by inducing histone deacetylation. XPC localizes to hypoacetylated chromatin domains in a DNA damage-independent manner, mediated by its structurally disordered middle (M) region. The M region interacts directly with the N-terminal tail of histone H3, an interaction compromised by H3 acetylation. Although the M region is dispensable for in vitro NER, it promotes DNA damage removal by GG-NER in vivo, particularly in the absence of UV-DDB. We propose that histone deacetylation around DNA damage facilitates the recruitment of XPC through the M region, contributing to efficient lesion recognition and initiation of GG-NER. [Display omitted] •Histone deacetylation by HDAC1/2 promotes the DNA lesion recognition by XPC•The HDAC1/2 activators, MTA proteins, also promote the recruitment of XPC•XPC tends to localize in hypoacetylated chromatin independently of DNA damage•Disordered middle region of XPC interacts with histone H3 tail and promotes GG-NER Molecular biology; Molecular interaction; Cell biology