Lessel, Davor ORCID: 0000-0003-4496-244X, Vaz, Bruno, Halder, Swagata, Lockhart, Paul J., Marinovic-Terzic, Ivana, Lopez-Mosqueda, Jaime, Philipp, Melanie ORCID: 0000-0003-2714-965X, Sim, Joe C. H., Smith, Katherine R., Oehler, Judith, Cabrera, Elisa, Freire, Raimundo ORCID: 0000-0003-4473-8894, Pope, Kate, Nahid, Amsha, Norris, Fiona, Leventer, Richard J., Delatycki, Martin B., Barbi, Gotthold, von Ameln, Simon ORCID: 0000-0002-2242-3165, Hoegel, Josef, Degoricija, Marina ORCID: 0000-0001-7023-9381, Fertig, Regina, Burkhalter, Martin D., Hofmann, Kay ORCID: 0000-0002-2289-9083, Thiele, Holger, Altmueller, Janine, Nuernberg, Gudrun, Nuernberg, Peter, Bahlo, Melanie ORCID: 0000-0001-5132-0774, Martin, George M., Aalfs, Cora M., Oshima, Junko, Terzic, Janos, Amor, David J., Dikic, Ivan ORCID: 0000-0001-8156-9511, Ramadan, Kristijan and Kubisch, Christian ORCID: 0000-0003-4220-0978 (2014). Mutations in SPRTN cause early onset hepatocellular carcinoma, genomic instability and progeroid features. Nature Genet., 46 (11). S. 1239 - 1245. NEW YORK: NATURE PUBLISHING GROUP. ISSN 1546-1718

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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)(1-7) 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(1-7). 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.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Lessel, DavorUNSPECIFIEDorcid.org/0000-0003-4496-244XUNSPECIFIED
Vaz, BrunoUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Halder, SwagataUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lockhart, Paul J.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Marinovic-Terzic, IvanaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lopez-Mosqueda, JaimeUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Philipp, MelanieUNSPECIFIEDorcid.org/0000-0003-2714-965XUNSPECIFIED
Sim, Joe C. H.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Smith, Katherine R.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Oehler, JudithUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Cabrera, ElisaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Freire, RaimundoUNSPECIFIEDorcid.org/0000-0003-4473-8894UNSPECIFIED
Pope, KateUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Nahid, AmshaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Norris, FionaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Leventer, Richard J.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Delatycki, Martin B.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Barbi, GottholdUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
von Ameln, SimonUNSPECIFIEDorcid.org/0000-0002-2242-3165UNSPECIFIED
Hoegel, JosefUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Degoricija, MarinaUNSPECIFIEDorcid.org/0000-0001-7023-9381UNSPECIFIED
Fertig, ReginaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Burkhalter, Martin D.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hofmann, KayUNSPECIFIEDorcid.org/0000-0002-2289-9083UNSPECIFIED
Thiele, HolgerUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Altmueller, JanineUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Nuernberg, GudrunUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Nuernberg, PeterUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Bahlo, MelanieUNSPECIFIEDorcid.org/0000-0001-5132-0774UNSPECIFIED
Martin, George M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Aalfs, Cora M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Oshima, JunkoUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Terzic, JanosUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Amor, David J.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Dikic, IvanUNSPECIFIEDorcid.org/0000-0001-8156-9511UNSPECIFIED
Ramadan, KristijanUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kubisch, ChristianUNSPECIFIEDorcid.org/0000-0003-4220-0978UNSPECIFIED
URN: urn:nbn:de:hbz:38-425253
DOI: 10.1038/ng.3103
Journal or Publication Title: Nature Genet.
Volume: 46
Number: 11
Page Range: S. 1239 - 1245
Date: 2014
Publisher: NATURE PUBLISHING GROUP
Place of Publication: NEW YORK
ISSN: 1546-1718
Language: English
Faculty: Faculty of Mathematics and Natural Sciences
Divisions: Faculty of Mathematics and Natural Sciences > Department of Biology > Institute for Genetics
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
DNA-DAMAGE; REPLICATION-FORK; TRANSLESION SYNTHESIS; DVC1 C1ORF124; SPARTAN/C1ORF124; CANCER; REGULATOR; CHECKPOINT; STRESS; GENEMultiple languages
Genetics & HeredityMultiple languages
Refereed: Yes
URI: http://kups.ub.uni-koeln.de/id/eprint/42525

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