Degadration of mismatch repair hMutSα heterodimer by the ubiquitin-proteasome pathway

Hernandez-Pigeon, Hélène; Laurent, Guy; Humbert, Odile; Salles, Bernard; Lautier, Dominique

doi:10.1016/S0014-5793(04)00181-4

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Volume 562, Issue 1 , Pages 40-44, 26 March 2004

Degadration of mismatch repair hMutSα heterodimer by the ubiquitin-proteasome pathway

Edited by Horst Feldmann

Hélène Hernandez-Pigeon
- INSERM U563, Centre de Physiopathologie Toulouse Purpan, Institut Claudius Regaud, 20 rue du Pont Saint-Pierre, 31052 Toulouse, France
Guy Laurent
- INSERM U563, Centre de Physiopathologie Toulouse Purpan, Institut Claudius Regaud, 20 rue du Pont Saint-Pierre, 31052 Toulouse, France
- Service d’Hématologie, Hôpital Purpan, Place du Dr. Baylac, 31059 Toulouse, France
Odile Humbert
- Institut de Pharmacologie et Biologie Structurale, UMR 5089 CNRS, 205 route de Narbonne, 31077 Toulouse, France
Bernard Salles
- Institut de Pharmacologie et Biologie Structurale, UMR 5089 CNRS, 205 route de Narbonne, 31077 Toulouse, France
Dominique Lautier
- INSERM U563, Centre de Physiopathologie Toulouse Purpan, Institut Claudius Regaud, 20 rue du Pont Saint-Pierre, 31052 Toulouse, France
- Corresponding author. Fax: (33)-561-42 46 06

Received 29 November 2003; received in revised form 30 January 2004; accepted 16 February 2004.

Abstract

Mismatch repair plays a critical role in genome stability. This process requires several proteins including hMSH2/hMSH6 (hMutSα) heterodimer involved in the first stage of the process, the mispair recognition. We previously reported that in U937 and HL-60 cell lines, hMSH2 and hMSH6 protein expression was much lower than that in HeLa and KG1a cells. Here, we showed that the decreased expression of hMutSα results from differences in the degradation rate of both proteins by the ubiquitin-proteasome pathway. Our data suggest that in human cell lines, ubiquitin-proteasome could play an important role in the regulation of hMutSα protein expression, thereby regulating mismatch repair activity.

Keywords: MSH2, MSH6, Ubiquitination, Protein stability, Mismatch repair, Proteasome

Abbreviations: CHX, cycloheximide, DCIC, dichloroisocoumarin, MCA, 7-amino-4-methylcoumarin, MMR, mismatch repair, MSI, microsatellite instability, RRL, rabbit reticulocyte lysate, TPCK, 1-chloro-3-tosylamido-4-phenyl-2-butanone, Ub, ubiquitin