RAD51D protects against MLH1-dependent cytotoxic responses to O(6)-methylguanine.

DNA Repair
Preeti RajeshDouglas L Pittman

Abstract

S(N)1-type methylating agents generate O(6)-methyl guanine (O(6)-meG), which is a potently mutagenic, toxic, and recombinogenic DNA adduct. Recognition of O(6)-meG:T mismatches by mismatch repair (MMR) causes sister chromatid exchanges, which are representative of homologous recombination (HR) events. Although the MMR-dependent mutagenicity and toxicity caused by O(6)-meG has been studied, the mechanisms of recombination induced by O(6)-meG are poorly understood. To explore the HR and MMR genetic interactions in mammals, we used the Rad51d and Mlh1 mouse models. Ablation of Mlh1 did not appreciably influence the developmental phenotypes conferred by the absence of Rad51d. Mouse embryonic fibroblasts (MEFs) deficient in Rad51d can only proliferate in p53-deficient background. Therefore, Rad51d(-/-)Mlh1(-/-)Trp53(-/-) MEFs with a combined deficiency of HR and MMR were generated and comparisons between MLH1 and RAD51D status were made. To our knowledge, these MEFs are the first mammalian model system for combined HR and MMR defects. Rad51d-deficient MEFs were 5.3-fold sensitive to N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) compared to the Rad51d-proficient MEFs. A pronounced G2/M arrest in Rad51d-deficient cells was accompanied b...Continue Reading

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Citations

Jan 13, 2012·Nature Reviews. Cancer·Dragony FuLeona D Samson
Dec 26, 2015·DNA Repair·Zhongdao LiPeggy Hsieh
Oct 16, 2012·International Journal of Cancer. Journal International Du Cancer·Pierre TennstedtKerstin Borgmann
Sep 26, 2017·Environmental and Molecular Mutagenesis·Michael D WyattDouglas L Pittman
Jul 12, 2014·The Journal of Biological Chemistry·Bo LinChristopher D Heinen
Sep 10, 2021·Nucleic Acids Research·Abhishek Bharadwaj SharmaEric Van Dyck

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