The Schizosaccharomyces pombe sirtuin Hst4, functions in the maintenance of genome stability by regulating histone H3 lysine56 acetylation (H3K56ac) and promoting cell survival during replicative stress. However, its molecular function in DNA damage survival is unclear. Here, we show that hst4 deficiency in the fission yeast causes S phase delay and DNA synthesis defects. We identified a novel functional link between hst4 and the replisome component mcl1 in a suppressor screen aimed to identify genes that could restore the slow growth and Methyl methanesulphonate (MMS) sensitivity phenotypes of the hst4Δ mutant. Expression of the replisome component Mcl1 rescues hst4Δ phenotypes. Interestingly, hst4 and mcl1 show an epistatic interaction and suppression of hst4Δ phenotypes by mcl1 is H3K56 acetylation dependent. Furthermore, Hst4 was found to regulate the expression of mcl1. Finally, we show that hSIRT2 depletion results in decreased levels of And-1 (human orthologue of Mcl1), establishing the conservation of this mechanism. Moreover, on induction of replication stress (MMS treatment), Mcl1 levels decrease upon Hst4 down regulation. Our results identify a novel function of Hst4 in regulation of DNA replication that is dependent on H3K56 acetylation. Both SIRT2 and And-1 are deregulated in cancers. Therefore, these findings could be of therapeutic importance in future.