Histone H3 lysine 36 methyltransferase mobilizes NER factors to regulate tolerance against alkylation damage in fission yeast

Abstract

The Set2 methyltransferase and its target, histone H3 lysine 36 (H3K36), affect chromatin architecture during the transcription and repair of DNA double-stranded breaks. Set2 also confers resistance against the alkylating agent, methyl methanesulfonate (MMS), through an unknown mechanism. Here, we show that Schizosaccharomyces pombe (S. pombe) exhibit MMS hypersensitivity when expressing a set2 mutant lacking the catalytic histone methyltransferase domain or a H3K36R mutant (reminiscent of a set2-null mutant). Set2 acts synergistically with base excision repair factors but epistatically with nucleotide excision repair (NER) factors, and determines the timely nuclear accumulation of the NER initiator, Rhp23, in response to MMS. Set2 facilitates Rhp23 recruitment to chromatin at the brc1 locus, presumably to repair alkylating damage and regulate the expression of brc1+ in response to MMS. Set2 also show epistasis with DNA damage checkpoint proteins; regulates the activation of Chk1, a DNA damage response effector kinase; and acts in a similar functional group as proteins involved in homologous recombination. Consistently, Set2 and H3K36 ensure the dynamicity of Rhp54 in DNA repair foci formation after MMS treatment. Overall, our results indicate a novel role for Set2/H3K36me in coordinating the recruitment of DNA repair machineries to timely manage alkylating damage.

Set2 histone methyltransferase regulates transcription coupled-nucleotide excision repair in yeast

“…While repair of the TS is slower in set2Δ mutant cells, loss of Set2 (or H3K36A) does not cause the same magnitude of repair defect as a rad26Δ mutant [40], suggesting Set2 functions to facilitate, but is not essential for, TC-NER. It has been recently reported that the Set2 homolog in S. pombe is also epistatic with NER factors in cells treated with methyl methanesulfonate (MMS), a DNA alkylating agent [53]. This observation can be explained by our finding that Set2 regulates TC-NER, since the TC-NER pathway may function to repair MMS-induced alkylation damage [54].…”

“…It has been recently reported that the Set2 homolog in S . pombe is also epistatic with NER factors in cells treated with methyl methanesulfonate (MMS), a DNA alkylating agent [ 53 ]. This observation can be explained by our finding that Set2 regulates TC-NER, since the TC-NER pathway may function to repair MMS-induced alkylation damage [ 54 ].…”

Structural and functional specificity of H3K36 methylation

“…The amino acid residues of the core histone proteins are heavily decorated with post-translational modifications (PTMs), particularly on the unstructured histone tail domains, and these modifications help to regulate chromatin compaction and govern the availability of docking sites for chromatin-modifying factors [ 1 , 6 ]. PTMs such as methylation, phosphorylation, acetylation, SUMOylation and ubiquitination occur via the transfer of chemical moieties onto specific residues of histone proteins [ 7 ] that engage in crosstalk and influence various DNA metabolic processes, including gene transcription [ 7 – 10 ], DNA damage repair [ 11 , 12 ], specialized chromosomal loci assembly [ 13 , 14 ], and cell cycle progression [ 15 – 18 ].…”

SIRT6 mono-ADP ribosylates KDM2A to locally increase H3K36me2 at DNA damage sites to inhibit transcription and promote repair

“…H3K36me3 also precisely localizes the DNA mismatch recognition hMSH3 and hMSH6 proteins onto chromatin [ 11 ]. In fission yeast, new results suggest that H3K36me3 is the major form of methylation on H3K36 to mediate tolerance to MMS [ 12 ]. Histone H3K36 dimethylation appears to influence NHEJ [ 13 , 14 ].…”