Processing of O6-methylguanine by mismatch correction in human cell extracts

Current Biology : CB
S CeccottiM Bignami

Abstract

Human cell extracts perform an aberrant form of DNA synthesis on methylated plasmids [1], which represents processing of O6-methylguanine (O6-meG). Here, we show that extracts of colorectal carcinoma cells with defects in the mismatch repair proteins that normally correct replication errors do not carry out this synthesis. hMSH2-defective LoVo cell extracts (hMSH for human MutS homologue) performed O6-meG-dependent DNA synthesis only after the addition of the purified hMutS alpha mismatch recognition complex. Processing of O6-meG by mismatch correction requires PCNA and therefore probably DNA polymerase delta and/or epsilon. Mismatch repair-defective cells withstand O6-meG in their DNA [2], making them tolerant to methylating agents. Methylation-tolerant HeLaMR clones, with a mutator phenotype and a defect in either mismatch recognition or correction in vitro, also performed little O6-meG-dependent DNA synthesis. Assays of pairwise combinations of tolerant and colorectal carcinoma cell extracts identified hMLH1 as the missing mismatch repair function in a group of tolerant clones. The absence of processing by extracts of methylation-tolerant cells provides the first biochemical evidence that lethality of DNA O6-meG derives from...Continue Reading

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Citations

Mar 4, 2000·International Journal of Cancer. Journal International Du Cancer·S FiumicinoM Bignami
Feb 3, 1998·Mutation Research·G AquilinaM Bignami
May 30, 2001·European Journal of Cancer : Official Journal for European Organization for Research and Treatment of Cancer (EORTC) [and] European Association for Cancer Research (EACR)·I FrouinA I Scovassi
Nov 1, 1996·Chemistry & Biology·P Karran, M Bignami
Feb 9, 2006·Chemical Reviews·Ravi R IyerPaul L Modrich
Dec 16, 1997·Proceedings of the National Academy of Sciences of the United States of America·B P EngelwardL D Samson
Oct 15, 1998·Proceedings of the National Academy of Sciences of the United States of America·H Flores-Rozas, R D Kolodner
Sep 15, 1999·Proceedings of the National Academy of Sciences of the United States of America·M J Hickman, L D Samson
Dec 24, 2009·The Journal of Biological Chemistry·Yiyong LiuPaul Modrich
Sep 23, 2008·Genes & Development·Rebecca C FryLeona D Samson
Nov 25, 1998·Proceedings of the National Academy of Sciences of the United States of America·P BertrandR D Kolodner
Apr 8, 2004·Molecular Cell·Mark J Hickman, Leona D Samson
Dec 11, 1999·Carcinogenesis·G AquilinaM Bignami
Sep 30, 2005·Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology·Jennifer A QuinnHenry S Friedman
Aug 1, 2002·Current Protocols in Toxicology·James A SwenbergRobert Schoonhoven
Aug 1, 1998·The Journal of Biological Chemistry·T R Waters, P F Swann
Oct 7, 2006·Human Cell·Katsutoshi KobayashiKatsuhiko Yanaga
Sep 24, 2004·DNA Repair·Finn DrabløsHans E Krokan
Jul 29, 2004·DNA Repair·Lovorka StojicJosef Jiricny
Oct 9, 2018·ACS Chemical Biology·Riley L SvecPaul J Hergenrother

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