Arabidopsis methylation elevated mutant 1 (mem1)mutants have elevated levels of global DNA meth-ylation.In this study,such mutant alleles showed increased sensitivity to methyl methanesulfonate(MMS).In mem1 mutants,an assortment of genes engaged in DNA damage response (DDR),espe-cially DNA-repair-associated genes,were largely upregulated without MMS treatment,suggestive of activation of the DDR pathway in them.Following MMS treatment,expression levels of multiple DNA-repair-associated genes in mem1 mutants were generally lower than in Col-0 plants,which accounted for the MMS-sensitive phenotype of the mem1 mutants.A group of DNA methylation pathway genes were upregulated in mem1 mutants under non-MMS-treated conditions,causing ele-vated global DNA methylation,especially in RNA-directed DNA methylation (RdDM)-targeted regions.Moreover,MEM1 seemed to help ATAXlA-TELANGIECTASIA MUTATED (ATM) and/or SUP-PRESSOR OF GAMMA RESPONSE 1 (SOG1) to fully activate/suppress transcription of a subset of genes regulated simultaneously by MEM1 and ATM and/or SOG1,because expression of such genes decreased/increased consistently in mem 1 and atm and/or sog1 mutants,but the decreases/increases in the mem1 mutants were not as dramatic as in the atm and/or sog1 mutants.Thus,our studies reveals roles of MEM1 in safeguarding genome,and inter-relationships among DNA damage,activation of DDR,DNA methylation/demethylation,and DNA repair.