Abstract
Recent studies have demonstrated that lysine acetylation of histones is crucial for nucleotide excision repair (NER) by relaxing the chromatin structure, which facilitates the recruitment of repair factors. However, few studies have focused on the contribution of histone deacetylases (HDAC) to NER. Here, we found that histone H3 Lys14 (H3K14) was deacetylated by HDAC3 after UV irradiation. Depletion of HDAC3 caused defects in cyclobutene pyrimidine dimer excision and sensitized cells to UV irradiation. HDAC3-depleted cells had impaired unscheduled DNA synthesis, but not recovery of RNA synthesis, which indicates that HDAC3 was required for global genome NER. Moreover, xeroderma pigmentosum, complementation group C (XPC) accumulation at the local UV-irradiated area was attenuated in HDAC3-depleted cells. In addition to the delay of XPC accumulation at DNA damage sites, XPC ubiquitylation was inhibited in HDAC3-depleted cells. These results suggest that the deacetylation of histone H3K14 by HDAC3 after UV irradiation contributes to XPC recruitment to DNA lesions to promote global genome NER. IMPLICATIONS: Involvement of histone deacetylation for XPC accumulation after UV irradiation indicates conversion of chromatin structure is essential for nucleotide excision repair in human cancer cells.
Highlights
Nucleotide excision repair (NER) is a versatile DNA repair system that removes various helix-destabilizing DNA lesions including UVinduced cyclobutane pyrimidine dimers (CPD), 6-4 photoproducts (64PP), and bulky chemical adducts [1,2,3]
We quantified histone H3K14 acetylation at local UV-irradiated areas generated by UV irradiation through a polycarbonate isopore membrane filter in cells depleted of each histone deacetylases (HDAC) by siRNA (Fig. 1)
These results indicate that histone H3K14 was deacetylated in UV-irradiated areas by HDAC1–3, which suggests that these HDACs are associated with the response to UV irradiation
Summary
Nucleotide excision repair (NER) is a versatile DNA repair system that removes various helix-destabilizing DNA lesions including UVinduced cyclobutane pyrimidine dimers (CPD), 6-4 photoproducts (64PP), and bulky chemical adducts [1,2,3]. NER is classified into transcription-coupled NER (TC-NER) and global genome NER (GG-NER) based on the recognition mechanism of DNA structure distortion [1,2,3]. In TC-NER, damaged sites are recognized when actively transcribing RNA polymerases II are stalled on the DNA strand. TC-NER of DNA damage is faster and more efficient from transcribed strands of actively expressed genes than nontranscribed strands and genomic regions. In GG-NER, xeroderma pigmentosum, complementation group C (XPC) and UV-damaged. Note: Supplementary data for this article are available at Molecular Cancer Research Online (http://mcr.aacrjournals.org/).
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