Abstract
Here we review our development of, and results with, high resolution studies on global genome nucleotide excision repair (GGNER) in Saccharomyces cerevisiae. We have focused on how GGNER relates to histone acetylation for its functioning and we have identified the histone acetyl tranferase Gcn5 and acetylation at lysines 9/14 of histone H3 as a major factor in enabling efficient repair. We consider results employing primarily MFA2 as a model gene, but also those with URA3 located at subtelomeric sequences. In the latter case we also see a role for acetylation at histone H4. We then go on to outline the development of a high resolution genome-wide approach that enables one to examine correlations between histone modifications and the nucleotide excision repair (NER) of UV-induced cyclobutane pyrimidine dimers throughout entire genomes. This is an approach that will enable rapid advances in understanding the complexities of how compacted chromatin in chromosomes is processed to access DNA damage and then returned to its pre-damaged status to maintain epigenetic codes.
Highlights
The seminal research of Smerdon [1,2,3] and Thoma [3,4], and the fact that in vitro core nucleotide excision repair (NER) factors could not repair DNA damage in chromatin [5], showed that chromatin influenced how NER operated in eukaryotic cells
These sub-pathways differ only in the means of detecting DNA damage; transcription coupled NER (TC-NER) relies on a RNA polymerase stalled at a cyclobutane pyrimidine dimers (CPDs) signalling that the CPD requires repair [23,24], whereas GG-NER in S. cerevisiae relies on a GG-NER-specific complex that is composed of Rad16/Rad7 and the autonomously replicating sequence binding factor I (Abf1) [25,26,27]
The first observation we made with respect to unravelling how NER requires chromatin change to operate effectively was that the absence of the yeast Histone acetyltranferase (HAT) Gcn5 conferred some UV sensitivity [11]
Summary
The seminal research of Smerdon [1,2,3] and Thoma [3,4], and the fact that in vitro core nucleotide excision repair (NER) factors could not repair DNA damage in chromatin [5], showed that chromatin influenced how NER operated in eukaryotic cells. TC-NER uniquely operates on the transcribed strand of transcriptionally active genes and GG-NER operates on the transcribed strand as well as on the non transcribed, plus on all transcriptionally silent regions of the genome These sub-pathways differ only in the means of detecting DNA damage; TC-NER relies on a RNA polymerase stalled at a CPD signalling that the CPD requires repair [23,24], whereas GG-NER in S. cerevisiae relies on a GG-NER-specific complex that is composed of Rad16/Rad and the autonomously replicating sequence binding factor I (Abf1) [25,26,27]. We have uncovered some covalent histone modifications that are linked to efficient GG-NER, determined how these relate to Swi/Snf activity and determined that they are facilitated by the GG-NER specific complex of Rad16/Rad and Abf1 From these observations we will propose a model to suggest how the GG-NER complex operates to govern the removal of UV-induced DNA damage from yeast chromosomes
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