Document Detail


Defective expression of the DNA mismatch repair protein, MLH1, alters G2-M cell cycle checkpoint arrest following ionizing radiation.
MedLine Citation:
PMID:  9485033     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
A role for the Mut L homologue-1 (MLH1) protein, a necessary component of DNA mismatch repair (MMR), in G2-M cell cycle checkpoint arrest after 6-thioguanine (6-TG) exposure was suggested previously. A potential role for MLH1 in G1 arrest and/or G1-S transition after damage was, however, not discounted. We report that MLH1-deficient human colon carcinoma (HCT116) cells showed decreased survival and a concomitant deficiency in G2-M cell cycle checkpoint arrest after ionizing radiation (IR) compared with genetically matched, MMR-corrected human colon carcinoma (HCT116 3-6) cells. Similar responses were noted between murine MLH1 knockout compared to wild-type primary embryonic fibroblasts. MMR-deficient HCT116 cells or embryonic fibroblasts from MLH1 knockout mice also demonstrated classic DNA damage tolerance responses after 6-TG exposure. Interestingly, an enhanced p53 protein induction response was observed in HCT116 3-6 (MLH1+) compared with HCT116 (MLH1-) cells after IR or 6-TG. Retroviral vector-mediated expression of the E6 protein did not, however, affect the enhanced G2-M cell cycle arrest observed in HCT116 3-6 compared with MLH1-deficient HCT116 cells. A role for MLH1 in G2-M cell cycle checkpoint control, without alteration in G1, after IR was also suggested by similar S-phase progression between irradiated MLH1-deficient and MLH1-proficient human or murine cells. Introduction of a nocodazole-induced G2-M block, which corrected the MLH1-mediated G2-M arrest deficiency in HCT116 cells, clearly demonstrated that HCT116 and HCT116 3-6 cells did not differ in G1 arrest or G1-S cell cycle transition after IR. Thus, our data indicate that MLH1 does not play a major role in G1 cell cycle transition or arrest. We also show that human MLH1 and MSH2 steady-state protein levels did not vary with damage or cell cycle changes caused by IR or 6-TG. MLH1-mediated G2-M cell cycle delay (caused by either MMR proofreading of DNA lesions or by a direct function of the MLH1 protein in cell cycle arrest) may be important for DNA damage detection and repair prior to chromosome segregation to eliminate carcinogenic lesions (possibly brought on by misrepair) in daughter cells.
Authors:
T W Davis; C Wilson-Van Patten; M Meyers; K A Kunugi; S Cuthill; C Reznikoff; C Garces; C R Boland; T J Kinsella; R Fishel; D A Boothman
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Publication Detail:
Type:  Journal Article; Research Support, U.S. Gov't, Non-P.H.S.; Research Support, U.S. Gov't, P.H.S.    
Journal Detail:
Title:  Cancer research     Volume:  58     ISSN:  0008-5472     ISO Abbreviation:  Cancer Res.     Publication Date:  1998 Feb 
Date Detail:
Created Date:  1998-03-19     Completed Date:  1998-03-19     Revised Date:  2007-11-15    
Medline Journal Info:
Nlm Unique ID:  2984705R     Medline TA:  Cancer Res     Country:  UNITED STATES    
Other Details:
Languages:  eng     Pagination:  767-78     Citation Subset:  IM    
Affiliation:
Department of Human Oncology, University of Wisconsin-Madison, 53792, USA.
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MeSH Terms
Descriptor/Qualifier:
Adaptor Proteins, Signal Transducing
Animals
Carrier Proteins
Cell Cycle / radiation effects*
Cell Survival
Cells, Cultured
Colonic Neoplasms / genetics*
DNA Repair
Fibroblasts
Humans
Mice
Mice, Knockout
Neoplasm Proteins / genetics,  physiology*
Nuclear Proteins
Thioguanine / pharmacology
Tumor Cells, Cultured
Tumor Suppressor Protein p53 / physiology
Grant Support
ID/Acronym/Agency:
90-DKHD-10/DK/NIDDK NIH HHS
Chemical
Reg. No./Substance:
0/Adaptor Proteins, Signal Transducing; 0/Carrier Proteins; 0/MLH1 protein, human; 0/Mlh1 protein, mouse; 0/Neoplasm Proteins; 0/Nuclear Proteins; 0/Tumor Suppressor Protein p53; 154-42-7/Thioguanine

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