| A CRM1-dependent nuclear export pathway is involved in the regulation of MutLα subcellular localization. | |
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MedLine Citation:
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PMID: 21064154 Owner: NLM Status: In-Data-Review |
Abstract/OtherAbstract:
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MutLα plays an essential role in DNA mismatch repair (MMR) and is additionally involved in other cellular mechanisms such as the regulation of cell cycle checkpoints and apoptosis. Therefore, not only germline MMR gene defects but also the subcellular localization of MutLα might be of importance for the development of Lynch syndrome. Recently, we showed that MutLα contains functional nuclear import sequences and is most frequently localized in the nucleus. Here, we demonstrate that MutLα can move bidirectionally towards the nuclear membrane. Using MutLα transfected HEK293T cells we observed a significant shift of MLH1 and PMS2 from the nucleus to the cytoplasm after irradiation or cisplatin treatment. We analyzed both proteins for potential nuclear export sequences (NES) and identified one functional Rev-type NES ((578)LFDLAMLAL) in the C-terminal part of MLH1 that facilitates export via the CRM1/exportin pathway. Moreover, an MLH1-NES mutation detected in a patient with Lynch syndrome showed normal MMR activity but led to significantly impaired cytoplasmic transport after actinomycin D treatment. These results indicate that MutLα is able to shuttle from the nucleus to the cytoplasm, probably signaling DNA damages to downstream pathways. In conclusion, not only a defective MMR but also impaired nucleo-cytoplasmic shuttling might result in the onset of Lynch syndrome. © 2010 Wiley-Liss, Inc. |
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Authors:
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Angela Brieger; Ronja Adam; Sandra Passmann; Guido Plotz; Stefan Zeuzem; Jörg Trojan |
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Publication Detail:
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Type: Journal Article |
Journal Detail:
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Title: Genes, chromosomes & cancer Volume: 50 ISSN: 1098-2264 ISO Abbreviation: Genes Chromosomes Cancer Publication Date: 2011 Feb |
Date Detail:
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Created Date: 2010-12-14 Completed Date: - Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 9007329 Medline TA: Genes Chromosomes Cancer Country: United States |
Other Details:
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Languages: eng Pagination: 59-70 Citation Subset: IM |
Affiliation:
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Medical Clinic I, Biomedical Research Laboratory, Goethe-University, Frankfurt a.M., Germany. |
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From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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