Regulation Of DNA Damage Response By Histone Gene Expression

High-frequency DNA damage in the organism is a potential cause of cancer and age-related disease.As the regulator of the normal cell and growth,the DNA damage repair pathways and related factors are the focus of our research.In recent years,researchers have extended the related field to other functional factors including non-coding RNA,p53 and histone modifiers.Moreover,the effect of chromatin structure on the recruitment of repair factors bound at DNA damage sites has been established.However,it remains unknown whether histones,the core components of the chromatin,have other functions involved in the DNA damage repair pathway beyond being posttranslationally modified,such as acetylation,methylation,phosphorylation,etc.Therefore,our research aims to explore the relationship between histone gene expression and DNA damage response and repair.Here,using Saccharomyces cerevisiae,as a model organism,we successfully constructed the histone overexpressed strain Gal(H3-H4)and deletion mutants(htf2Δ,htab1Δ,htf2Δhtab1Δ,htf2Δhtab1Δ).Gal strain with higher histone levels grew better in the YPD addition of MMS(Methyl Methanesulfonate),while htf2Δ with lower histone levels grew slower underthe same condition.This result demonstrates that there is indeed a relationship between histone expression and DNA damage response and repair.To get further clues,we examined the spt10Δ,which can bind the UAS element in the histone gene locus to promote histone gene transcription.It is clearly that the mutant grew very slowly in the YPD addition of MMS compared to wild type suggesting that histone expression regulators have involved in regulating DNA damage response.To identify histone residues that regulate histone gene expression and DNA damage,we screened four histone mutants and found 13 sites including H2AL56A、H2AE65A、H2AL66A、H2AK76A、H2AL94A、H2AG107A、H2AS121A、H2BK111A、H3K14A、H3K56A、H3F104、H4L37A、H4K44A,correlating with our theory.Finally,to figure out the mechanism in H3K14 A,we deleted the GCN5 in yeast and found that like H3K14 A,the gcn5Δ mutant grew worse on MMS plates,which indicates that Gcn5-catylazed H3K14 ac regulates the DNA damage through histone expression.Our work will insights into the regulation of DNA damage response by histone gene expression.