Fission yeast sirtuin hst4 functions in preserving genomic integrity by regulating replisome component mcl1

Konada, Lahiri and Arichota, Shalini and Vadla, Raghavendra (2017) Fission yeast sirtuin hst4 functions in preserving genomic integrity by regulating replisome component mcl1. Scientific Reports. ISSN 2045-2322 (In Press)

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Abstract

The fission yeast Schizosaccharomyces pombe sirtuin Hst4 maintains genome stability by regulating histone H3 lysine56 acetylation (H3K56 acetylation) and promotes cell survival during replicative stress. However, its molecular function in DNA damage survival is unclear. Here, we show that hst4 deficiency causes S phase delay and DNA synthesis defects. We identified a novel functional link between hst4 and replisome component mcll by performing a suppressor screen to identify genes that restore slow growth and Methyl methane sulphonate sensitivity phenotypes of hst4'Jmutants. We show that expression of replisome component Mcll rescues hst-i] deletion phenotypes. Interestingly, hst4 and mcll show epistatic interaction and the suppression of hst4C Jphenotypes by expression of mcll is dependent on H3K56 acetylation. Further, we show that Hst4 regulates the expression of mcll. Finally, we present data showing that human SIRT2 depletion results in decreased levels of And-l(human orthologue of Mcll), establishing conservation of this mechanism in mammals. Strikingly, Mcll levels decrease when Hst4 is downregulated on replication stress. Our results identify a novel function of Hst4 in regulation of DNA transactions which is dependent on H3K56 acetylation. Both SIRT2 and And-l are deregulated in cancers. Therefore, these findings could be of therapeutic importance in future.

Item Type: Article
Subjects: Research > Research Center - Health Sciences
Depositing User: KMC Library
Date Deposited: 05 Feb 2018 06:24
Last Modified: 05 Feb 2018 06:24
URI: http://eprints.manipal.edu/id/eprint/150553

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