Abstract
Global genome nucleotide excision repair removes DNA damage from transcriptionally silent regions of the genome. Relatively little is known about the molecular events that initiate and regulate this process in the context of chromatin. We've shown that, in response to UV radiation–induced DNA damage, increased histone H3 acetylation at lysine 9 and 14 correlates with changes in chromatin structure, and these alterations are associated with efficient global genome nucleotide excision repair in yeast. These changes depend on the presence of the Rad16 protein. Remarkably, constitutive hyperacetylation of histone H3 can suppress the requirement for Rad7 and Rad16, two components of a global genome repair complex, during repair. This reveals the connection between histone H3 acetylation and DNA repair. Here, we investigate how chromatin structure is modified following UV irradiation to facilitate DNA repair in yeast. Using a combination of chromatin immunoprecipitation to measure histone acetylation levels, histone acetylase occupancy in chromatin, MNase digestion, or restriction enzyme endonuclease accessibility assays to analyse chromatin structure, and finally nucleotide excision repair assays to examine DNA repair, we demonstrate that global genome nucleotide excision repair drives UV-induced chromatin remodelling by controlling histone H3 acetylation levels in chromatin. The concerted action of the ATPase and C3HC4 RING domains of Rad16 combine to regulate the occupancy of the histone acetyl transferase Gcn5 on chromatin in response to UV damage. We conclude that the global genome repair complex in yeast regulates UV-induced histone H3 acetylation by controlling the accessibility of the histone acetyl transferase Gcn5 in chromatin. The resultant changes in histone H3 acetylation promote chromatin remodelling necessary for efficient repair of DNA damage. Recent evidence suggests that GCN5 plays a role in NER in human cells. Our work provides important insight into how GG-NER operates in chromatin.
Highlights
DNA repair is a central facet of DNA metabolism, and nucleotide excision repair (NER) is an important component of a complex cellular response that prevents the loss of genetic information caused by DNA damage
Acetylation of histone H3 after UV irradiation depends on the presence of Rad16 and this process is necessary for efficient global genome nucleotide excision repair (GG-NER) [10]
Since UV induced histone H3 acetylation correlates with efficient GGNER and elevated levels of histone H3 acetylation at MFA2 suppress the requirement for Rad7 and Rad16 during GG-NER [10], this poses the question as to how Rad7 and Rad16 control histone H3 acetylation
Summary
DNA repair is a central facet of DNA metabolism, and nucleotide excision repair (NER) is an important component of a complex cellular response that prevents the loss of genetic information caused by DNA damage. Its importance for the repair of ultraviolet (UV) light induced DNA lesions is dramatically illustrated in humans who suffer from the autosomal recessive disease xeroderma pigmentosum (XP). Chromatin has a major impact on DNA metabolic processes by controlling the functional interaction of proteins with regulatory and other elements in the DNA [4,5]. Chromatin remodelling and histone modification are two major mechanisms that contribute to this regulation. Both processes have roles in controlling gene transcription [6,7] and in NER [8,9,10]
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