biostudies-literatureUnknown25(4)Kusakabe MJapan Society for the Promotion of ScienceThe 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 <i>in vitro</i> NER, it promotes DNA damage removal by GG-NER <i>in vivo</i>, 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.iScience104040https://www.ebi.ac.uk/biostudies/studies/S-EPMC8938288biostudies-literatureHistone deacetylation regulates nucleotide excision repair through an interaction with the XPC protein.PMC8938288Sakai WTsuchida KKakumu EMatsuda TMaeda TSugasawa KKurihara FTada HNakao MYokoi MKusakabe MKato AYasuda TKusao KfalseHistone 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 <i>in vitro</i> NER, it promotes DNA damage removal by GG-NER <i>in vivo</i>, 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.2022-01-01T00:00:00Z2022 Apr2025-04-26T04:39:49.964Z2025-04-26T04:39:49.964ZS-EPMC89382883533068710.1016/j.isci.2022.104040