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.
Pubmed ID: 21698136 RIS Download
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It is now widely known that animals share many genes with humans and can suffer from the same diseases, for example diabetes or deafness. Investigating these diseases in animals can provide vital leads to understanding both their causes and ways to treat them in humans. This approach to medical research lies at the heart of work at the MRC Mammalian Genetics Unit (MGU) at Harwell in Oxfordshire. In 1995 the MRC Radiobiology Unit was reconstituted to form two new units, the Radiation and Genome Stability Unit and the MGU. These opened in January 1996, together with the UK Mouse Genome Centre which is now part of MGU, making MRC Harwell a unique campus for multi-disciplinary genetics research. Since MGU's Director Steve Brown took the reins in 1996, the unit has dramatically expanded its scientific scope and increased its personnel from 40 to over 100. It now has 13 research programs encompassing molecular genetics, genomics, genetic manipulation and data analysis at all levels, from single genes to the whole genome. With a combination of cutting-edge facilities and expertise unrivaled in Europe, MGU Harwell has become firmly established as one of the world's leading academic centres for mouse genetics.
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