title: hMSH5 is a nucleocytoplasmic shuttling protein whose stability depends on its subcellular localization.
abstract: MSH5 is a MutS-homologous protein required for meiotic DNA recombination. In addition, recent studies suggest that the human MSH5 protein (hMSH5) participates to mitotic recombination and to the cellular response to DNA damage and thus raise the possibility that a tight control of hMSH5 function(s) may be important for genomic stability. With the aim to characterize mechanisms potentially involved in the regulation of hMSH5 activity, we investigated its intracellular trafficking properties. We demonstrate that hMSH5 possesses a CRM1-dependent nuclear export signal (NES) and a nuclear localization signal that participates to its nuclear targeting. Localization analysis of various mutated forms of hMSH5 by confocal microscopy indicates that hMSH5 shuttles between the nucleus and the cytoplasm. We also provide evidence suggesting that hMSH5 stability depends on its subcellular compartmentalization, hMSH5 being much less stable in the nucleus than in the cytoplasm. Together, these data suggest that hMSH5 activity may be regulated by nucleocytoplasmic shuttling and nuclear proteasomal degradation, both of these mechanisms contributing to the control of nuclear hMSH5 content. Moreover, data herein also support that in tissues where both hMSH5 and hMSH4 proteins are expressed, hMSH5 might be retained in the nucleus through masking of its NES by binding of hMSH4.
authors.affiliation: FRE 3086 Instabilité génétique: Maladies rares et cancers, Université de Nice Sophia-Antipolis, CNRS, Nice Cedex 2, France.
authors.forename: François
authors.initials: F
authors.lastname: Lahaye
authors.forename: Françoise
authors.initials: F
authors.lastname: Lespinasse
authors.forename: Pascal
authors.initials: P
authors.lastname: Staccini
authors.forename: Lucile
authors.initials: L
authors.lastname: Palin
authors.forename: Véronique
authors.initials: V
authors.lastname: Paquis-Flucklinger
authors.forename: Sabine
authors.initials: S
authors.lastname: Santucci-Darmanin
mesh_terms: D021581:Active Transport, Cell Nucleus; D000595:Amino Acid Sequence; D001483:Base Sequence; D018797:Cell Cycle Proteins / Q000032:analysis / Q000737:chemistry* / Q000378:metabolism*; D002467:Cell Nucleus / Q000378:metabolism*; D017124:Conserved Sequence; D005231:Fatty Acids, Unsaturated / Q000494:pharmacology; D006367:HeLa Cells; D006801:Humans; D008969:Molecular Sequence Data; D049790:Nuclear Export Signals; D019913:Nuclear Localization Signals; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D021381:Protein Transport
chemical_list: D018797:Cell Cycle Proteins; D005231:Fatty Acids, Unsaturated; C409221:MSH4 protein, human; C118481:MSH5 protein, human; D049790:Nuclear Export Signals; D019913:Nuclear Localization Signals; D046988:Proteasome Endopeptidase Complex; C038753:leptomycin B