| Literature DB >> 25261934 |
Davor Lessel1, Bruno Vaz2, Swagata Halder3, Paul J Lockhart4, Ivana Marinovic-Terzic5, Jaime Lopez-Mosqueda6, Melanie Philipp7, Joe C H Sim8, Katherine R Smith9, Judith Oehler3, Elisa Cabrera10, Raimundo Freire10, Kate Pope8, Amsha Nahid11, Fiona Norris12, Richard J Leventer13, Martin B Delatycki14, Gotthold Barbi15, Simon von Ameln15, Josef Högel15, Marina Degoricija5, Regina Fertig16, Martin D Burkhalter17, Kay Hofmann18, Holger Thiele19, Janine Altmüller19, Gudrun Nürnberg19, Peter Nürnberg20, Melanie Bahlo21, George M Martin22, Cora M Aalfs23, Junko Oshima22, Janos Terzic5, David J Amor4, Ivan Dikic6, Kristijan Ramadan3, Christian Kubisch1.
Abstract
Age-related degenerative and malignant diseases represent major challenges for health care systems. Elucidation of the molecular mechanisms underlying carcinogenesis and age-associated pathologies is thus of growing biomedical relevance. We identified biallelic germline mutations in SPRTN (also called C1orf124 or DVC1) in three patients from two unrelated families. All three patients are affected by a new segmental progeroid syndrome characterized by genomic instability and susceptibility toward early onset hepatocellular carcinoma. SPRTN was recently proposed to have a function in translesional DNA synthesis and the prevention of mutagenesis. Our in vivo and in vitro characterization of identified mutations has uncovered an essential role for SPRTN in the prevention of DNA replication stress during general DNA replication and in replication-related G2/M-checkpoint regulation. In addition to demonstrating the pathogenicity of identified SPRTN mutations, our findings provide a molecular explanation of how SPRTN dysfunction causes accelerated aging and susceptibility toward carcinoma.Entities:
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Year: 2014 PMID： 25261934 PMCID： PMC4343211 DOI： 10.1038/ng.3103
Source DB: PubMed Journal: Nat Genet ISSN： 1061-4036 Impact factor: 38.330