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Interactions of the DNA mismatch repair proteins MLH1 and MSH2 with c-MYC and MAX

Oncogene volume 22, pages 819–825 (2003)Cite this article

Abstract

MSH2 and MLH1 have a central role in correcting mismatches in DNA occurring during DNA replication and have been implicated in the engagement of apoptosis induced by a number of cytotoxic anticancer agents. The function of MLH1 is not clearly defined, although it is required for mismatch repair (MMR) and engagement of apoptosis after certain types of DNA damage. In order to identify other partners of MLH1 that may be involved in signalling MMR or apoptosis, we used human MLH1 in yeast two-hybrid screens of normal human breast and ovarian cDNA libraries. As well as known partners of MLH1 such as PMS1, MLH3 and MBD4, we identified the carboxy terminus of the human c-MYC proto-oncogene as an interacting sequence. We demonstrate, both in vitro by yeast two-hybrid and GST-fusion pull-down experiments, as well as in vivo by coimmunoprecipitation from human tumour cell extracts, that MLH1 interacts with the c-MYC protein. We further demonstrate that the heterodimeric partner of c-MYC, MAX, interacts with a different MMR protein, MSH2, both in vitro and in vivo. Using an inducible c-MYC-ER™ fusion gene, we show that elevated c-MYC expression leads to an increased HGPRT mutation rate of Rat1 cells and an increase in the number of frameshift mutants at the HGPRT locus. The effect on HGPRT mutation rate is small (2–3-fold), but is consistent with deregulated c-MYC expression partially inhibiting MMR activity.

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Acknowledgements

We would like to thank Dr RN Eisenman (Seattle, WA, USA) for the pHLmyc0/1 plasmid. The MYC-ER™ cell line was kindly supplied by Dr Evan (San Francisco, CA, USA). AGH and ECM acknowledge funding from the LRF and NECCRF. EH is AICR funded and HR funded by a Glasgow University scholarship. Cancer Research UK funded MM, CJM, DHC, DAFG and RB.

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  1. Stephen T Durant

    Present address: Clare Hall, South Mimms, UK

Authors and Affiliations

  1. Department of Medical Oncology, Glasgow University, Glasgow, G61 1BD, UK

    Mary Mac Partlin, Elizabeth Homer, Helen Robinson, Carol J McCormick, Stephen T Durant & Robert Brown

  2. Beatson Institute for Cancer Research, Cancer Research UK Beatson Laboratories, Garscube Estate, Glasgow, G61 1BD, UK

    David AF Gillespie

  3. Leukaemia Research Group, Cancer Research Unit, Medical School, Framlington Place, University of Newcastle upon Tyne, NE2 4HH, UK

    Elizabeth C Matheson & Andrew G Hall

  4. Biomedical Research Centre, University of Dundee, Ninewells Hospital & Medical School, DD1 9SY, Dundee, UK

    Dorothy H Crouch

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  1. Mary Mac Partlin
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Correspondence to Robert Brown.

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Partlin, M., Homer, E., Robinson, H. et al. Interactions of the DNA mismatch repair proteins MLH1 and MSH2 with c-MYC and MAX. Oncogene 22, 819–825 (2003). https://doi.org/10.1038/sj.onc.1206252

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