title: The Major Replicative Histone Chaperone CAF-1 Suppresses the Activity of the DNA Mismatch Repair System in the Cytotoxic Response to a DNA-methylating Agent.
abstract: The DNA mismatch repair (MMR) system corrects DNA mismatches in the genome. It is also required for the cytotoxic response of O6-methylguanine-DNA methyltransferase (MGMT)-deficient mammalian cells and yeast mgt1Δ rad52Δ cells to treatment with Sn1-type methylating agents, which produce cytotoxic O6-methylguanine (O6-mG) DNA lesions. Specifically, an activity of the MMR system causes degradation of irreparable O6-mG-T mispair-containing DNA, triggering cell death; this process forms the basis of treatments of MGMT-deficient cancers with Sn1-type methylating drugs. Recent research supports the view that degradation of irreparable O6-mG-T mispair-containing DNA by the MMR system and CAF-1-dependent packaging of the newly replicated DNA into nucleosomes are two concomitant processes that interact with each other. Here, we studied whether CAF-1 modulates the activity of the MMR system in the cytotoxic response to Sn1-type methylating agents. We found that CAF-1 suppresses the activity of the MMR system in the cytotoxic response of yeast mgt1Δ rad52Δ cells to the prototypic Sn1-type methylating agent N-methyl-N'-nitro-N-nitrosoguanidine. We also report evidence that in human MGMT-deficient cell-free extracts, CAF-1-dependent packaging of irreparable O6-mG-T mispair-containing DNA into nucleosomes suppresses its degradation by the MMR system. Taken together, these findings suggest that CAF-1-dependent incorporation of irreparable O6-mG-T mispair-containing DNA into nucleosomes suppresses its degradation by the MMR system, thereby defending the cell against killing by the Sn1-type methylating agent.
authors.affiliation: From the Department of Biochemistry and Molecular Biology, Southern Illinois University, School of Medicine, Carbondale, Illinois 62901.
authors.forename: Lyudmila Y
authors.initials: LY
authors.lastname: Kadyrova
authors.affiliation: From the Department of Biochemistry and Molecular Biology, Southern Illinois University, School of Medicine, Carbondale, Illinois 62901.
authors.forename: Basanta K
authors.initials: BK
authors.lastname: Dahal
authors.affiliation: From the Department of Biochemistry and Molecular Biology, Southern Illinois University, School of Medicine, Carbondale, Illinois 62901 fkadyrov@siumed.edu.
authors.forename: Farid A
authors.initials: FA
authors.lastname: Kadyrov
mesh_terms: D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D001761:Bleomycin / Q000494:pharmacology; D019175:DNA Methylation / Q000187:drug effects*; D053843:DNA Mismatch Repair / Q000187:drug effects*; D015966:Gene Expression Regulation, Fungal / Q000187:drug effects*; D057809:HEK293 Cells; D006801:Humans; D008769:Methylnitronitrosoguanidine / Q000494:pharmacology; D012260:Ribonucleases / Q000378:metabolism*; D012441:Saccharomyces cerevisiae / Q000187:drug effects / Q000378:metabolism*; D029701:Saccharomyces cerevisiae Proteins / Q000378:metabolism*
chemical_list: D000903:Antibiotics, Antineoplastic; D029701:Saccharomyces cerevisiae Proteins; D001761:Bleomycin; D008769:Methylnitronitrosoguanidine; D012260:Ribonucleases; C079009:POP2 protein, S cerevisiae
keywords: DNA mismatch repair; DNA replication; cancer; genomic instability; histone chaperone; mutL homolog 1 (MLH1)