Journal Article

Mismatch repair, G<sub>2</sub>/M cell cycle arrest and lethality after DNA damage

Gabriele Aquilina, Marco Crescenzi and Margherita Bignami

in Carcinogenesis

Volume 20, issue 12, pages 2317-2326
Published in print December 1999 | ISSN: 0143-3334
Published online December 1999 | e-ISSN: 1460-2180 | DOI: http://dx.doi.org/10.1093/carcin/20.12.2317
Mismatch repair, G2/M cell cycle arrest and lethality after DNA damage

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The role of the mismatch repair pathway in DNA replication is well defined but its involvement in processing DNA damage induced by chemical or physical agents is less clear. DNA repair and cell cycle control are tightly linked and it has been suggested that mismatch repair is necessary to activate the G2/M checkpoint in the presence of certain types of DNA damage. We investigated the proposed role for mismatch repair (MMR) in activation of the G2/M checkpoint following exposure to DNA-damaging agents. We compared the response of MMR-proficient HeLa and Raji cells with isogenic variants defective in either the hMutLα or hMutSα complex. Different agents were used: the cross-linker N-(2-chloroethyl)-N′-cyclohexyl-N-nitrosourea (CCNU), γ-radiation and the monofunctional methylating agent N-methyl-N-nitrosourea (MNU). MMR-defective cells are relatively sensitive to CCNU, while no differences in survival between repair-proficient and -deficient cells were observed after exposure to γ-radiation. Analysis of cell cycle distribution indicates that G2 arrest is induced at least as efficiently in MMR-defective cells after exposure to either CCNU or ionizing radiation. As expected, MNU does not induce G2 accumulation in MMR-defective cells, which are known to be highly tolerant to killing by methylating agents, indicating that MNU-induced cell cycle alterations are strictly dependent on the cytotoxic processing of methylation damage by MMR. Conversely, activation of the G2/M checkpoint after DNA damage induced by CCNU and γ-radiation does not depend on functional MMR. In addition, the absence of a simple correlation between the extent of G2 arrest and cell killing by these agents suggests that G2 arrest reflects the processing by MMR of both lethal and non-lethal DNA damage.

Keywords: CCNU, N-(2-chloroethyl)-N′-cyclohexyl-N-nitrosourea; FCS, fetal calf serum; ICL, interstrand DNA cross-links; MMR, mismatch repair; MMR–, MMR-defective; MMR+, MMR-proficient; MNNG, N-methyl-N′-nitro-N-nitrosoguanidine; MNU, N-methyl-N-nitrosourea; O6-meGua, O6-methylguanine; 6-TG, 6-thioguanine.

Journal Article.  6089 words.  Illustrated.

Subjects: Clinical Cytogenetics and Molecular Genetics

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