Histone H3 K79 methylation states play distinct roles in UV-induced sister chromatid exchange and cell cycle checkpoint arrest in Saccharomyces cerevisiae

Abstract

Histone post-translational modifications have been shown to contribute to DNA damage repair. Prior studies have suggested that specific H3K79 methylation states play distinct roles in the response to UV-induced DNA damage. To evaluate these observations, we examined the effect of altered H3K79 methylation patterns on UV-induced G1/S checkpoint response and sister chromatid exchange (SCE). We found that the di- and trimethylated states both contribute to activation of the G1/S checkpoint to varying degrees, depending on the synchronization method, although methylation is not required for checkpoint in response to high levels of UV damage. In contrast, UV-induced SCE is largely a product of the trimethylated state, which influences the usage of gene conversion versus popout mechanisms. Regulation of H3K79 methylation by H2BK123 ubiquitylation is important for both checkpoint function and SCE. H3K79 methylation is not required for the repair of double-stranded breaks caused by transient HO endonuclease expression, but does play a modest role in survival from continuous exposure. The overall results provide evidence for the participation of H3K79 methylation in UV-induced recombination repair and checkpoint activation, and further indicate that the di- and trimethylation states play distinct roles in these DNA damage response pathways.

Direct screening for chromatin status on DNA barcodes in yeast delineates the regulome of H3K79 methylation by Dot1

“…Another interesting point is the function of this regulation. Dot1 has been shown to function in several DNA repair pathways; it mediates checkpoint activation and recombinational repair after UV damage, and represses translesion synthesis (Conde and San-Segundo, 2008; Rossodivita et al, 2014). Dot1 has not yet been studied in the context of replication fork stalling, but our finding that H3K79 methylation is regulated in this context warrants further investigations.…”

Histone modifications in DNA damage response

“…In addition, H3K79 methylation mediated by Dot1L promotes nucleotide excision repair, and H3K79R mutation increases the binding of histone deacetylase complex to eliminate histone acetylation and reduce DNA lesion accessibility to repair enzymes (Chaudhuri et al, 2009;Tatum and Li, 2011). Moreover, Dot1L and H3K79me3 contribute to favorable sister chromatid exchange during HR and facilitate HR repair (Conde et al, 2009;Rossodivita et al, 2014). Furthermore, there is crosstalk between H3K79 methylation and other histone methylations.…”

Biological function and regulation of histone and non-histone lysine methylation in response to DNA damage

“…During replication, H3K79 methylation-mediated Rad9 recruitment contributes to sister chromatid recombination repair by regulating cohesion binding to damage sites [102]. H3K79me3 largely contributes to UV-induced sister chromatid exchange [103]. In addition, Dot1-dependent H3K79 methylation modulates the resistance to the alkylating agent MMS in translesion synthesis regulation, thereby maintains genome integrity [104][105][106].…”