Somatic MED12 Nonsense Mutation Escapes mRNA Decay and Reveals a Motif Required for Nuclear Entry
| Autor: | Markku Varjosalo, Xiaonan Liu, Pia Vahteristo, Salla Keskitalo, Satu Mustjoki, Mikko P. Turunen, Netta Mäkinen, Matias Kinnunen, Mika Kontro, Pernilla von Nandelstadh, Kaisa Lehti, Ville Rantanen, Jussi Taipale, Caroline A. Heckman, Esa Pitkänen, Kati Kämpjärvi, Tuomas Heikkinen, Heikki Kuusanmäki |
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| Přispěvatelé: | Research Programs Unit, Genome-Scale Biology (GSB) Research Program, University of Helsinki, Medicum, Department of Medical and Clinical Genetics, Institute of Biotechnology, Department of Pathology, Sampsa Hautaniemi / Principal Investigator, Lauri Antti Aaltonen / Principal Investigator, Institute for Molecular Medicine Finland, Clinicum, Department of Oncology, Hematologian yksikkö, Department of Medicine, HUS Comprehensive Cancer Center, Jussi Taipale / Principal Investigator, Kaisa Irene Lehti / Principal Investigator, Molecular Systems Biology |
| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Pore complex UTERINE LEIOMYOMAS DNA Mutational Analysis Nonsense mutation Mutant nonsense mutation Biology RNA Transport DISEASE PORE COMPLEX 03 medical and health sciences Exon acute lymphoblastic leukemia (ALL) Genetics Humans Missense mutation NLS Amino Acid Sequence MEDIATOR Nucleotide Motifs BioID Nuclear pore Alleles Genetics (clinical) Mediator Complex CHRONIC LYMPHOCYTIC-LEUKEMIA affinity purification mass spectrometry 1184 Genetics developmental biology physiology CANCER Molecular biology Nonsense Mediated mRNA Decay MED12 030104 developmental biology Amino Acid Substitution Codon Nonsense Protein Biosynthesis 3111 Biomedicine Nuclear localization sequence |
| Zdroj: | Human Mutation. 38:269-274 |
| ISSN: | 1059-7794 |
| Popis: | MED12 is a key component of the transcription-regulating Mediator complex. Specific missense and in-frame insertion/deletion mutations in exons 1 and 2 have been identified in uterine leiomyomas, breast tumors, and chronic lymphocytic leukemia. Here, we characterize the first MED12 5 end nonsense mutation (c.97G > T, p.E33X) identified in acute lymphoblastic leukemia and show that it escapes nonsense-mediated mRNA decay (NMD) by using an alternative translation initiation site. The resulting N-terminally truncated protein is unable to enter the nucleus due to the lack of identified nuclear localization signal (NLS). The absence of NLS prevents the mutant MED12 protein to be recognized by importin- and subsequent loading into the nuclear pore complex. Due to this mislocalization, all interactions between the MED12 mutant and other Mediator components are lost. Our findings provide new mechanistic insights into the MED12 functions and indicate that somatic nonsense mutations in early exons may avoid NMD. (C) 2017 Wiley Periodicals, Inc. |
| Databáze: | OpenAIRE |
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