title: Competency in mismatch repair prohibits clonal expansion of cancer cells treated with N-methyl-N'-nitro-N-nitrosoguanidine.
abstract: The phenomenon of alkylation tolerance has been observed in cells that are deficient in some component of the DNA mismatch repair (MMR) system. An alkylation-induced cell cycle arrest had been reported previously in one MMR-proficient cell line, whereas a MMR-defective clone derived from this line escapes from this arrest. We examined human cancer cell lines to determine if the cell cycle arrest were dependent upon the MMR system. Growth characteristics and cell cycle analysis after MNNG treatment were ascertained in seven MMR-deficient and proficient cell lines, with and without confirmed mutations in hMLH1 or hMSH2 by an in vitro transcription/translation assay. MMR-proficient cells underwent growth arrest in the G2 phase of the cell cycle after the first S phase, whereas MMR-deficient cells escaped an initial G2 delay and resumed a normal growth pattern. In the HCT116 line corrected for defective MMR by chromosome 3 transfer, the G2 phase arrest lasted more than five days. In another MMR-proficient colon cancer cell line, SW480, cell death occurred five days after MNNG treatment. A competent MMR system appears to be necessary for G2 arrest or cell death after alkylation damage, and this cell cycle checkpoint may allow the cell to repair damaged DNA, or prevent the replication of mutated DNA by prohibiting clonal expansion.
authors.affiliation: Division of Gastroenterology, Department of Medicine, University of California, San Diego 92093-0688, USA.
authors.forename: J M
authors.initials: JM
authors.lastname: Carethers
authors.forename: M T
authors.initials: MT
authors.lastname: Hawn
authors.forename: D P
authors.initials: DP
authors.lastname: Chauhan
authors.forename: M C
authors.initials: MC
authors.lastname: Luce
authors.forename: G
authors.initials: G
authors.lastname: Marra
authors.forename: M
authors.initials: M
authors.lastname: Koi
authors.forename: C R
authors.initials: CR
authors.lastname: Boland
mesh_terms: D000477:Alkylating Agents / Q000494:pharmacology; D002277:Carcinoma; D003110:Colonic Neoplasms; D004249:DNA Damage; D004260:DNA Repair; D004268:DNA-Binding Proteins; D005260:Female; D016195:G2 Phase / Q000187:drug effects*; D006801:Humans; D008769:Methylnitronitrosoguanidine / Q000494:pharmacology*; D008957:Models, Genetic; D051718:MutS Homolog 2 Protein; D009369:Neoplasms / Q000235:genetics*; D010051:Ovarian Neoplasms; D011518:Proto-Oncogene Proteins / Q000235:genetics; D012333:RNA, Messenger / Q000032:analysis; D017384:Sequence Deletion; D013234:Stem Cells; D014407:Tumor Cells, Cultured
chemical_list: D000477:Alkylating Agents; D004268:DNA-Binding Proteins; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger; D008769:Methylnitronitrosoguanidine; C497172:MSH2 protein, human; D051718:MutS Homolog 2 Protein