Journal
NATURE GENETICS
Volume 46, Issue 11, Pages 1239-1244Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/ng.3103
Keywords
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Categories
Funding
- Deutsche Forschungsgemeinschaft
- Cluster of Excellence 'Macromolecular Complexes' of Goethe University Frankfurt [EXC115]
- Landes-Offensive zur Entwicklung Wissenschaftlich-okonomischer Exzellenz program Ubiquitin Networks of the State of Hesse, Germany
- European Research Council under the European Union's Seventh Framework Programme/European Research Council [250241-LineUb]
- European Commission (Marie Curie Reintegration) [268333]
- Deutsche Stiftung far Herzforschung
- Medical Research Council [MC_PC_ 12001/1]
- Swiss National Science Foundation [31003A_141197]
- US National Institutes of Health (NIH) National Cancer Institute [R24CA78088, R24AG042328]
- NIH National Institute on Aging [R21AG033313]
- Ellison Medical Foundation
- German Research Foundation (DFG)
- EMBO long-term fellowship
- Croatian Ministry of Science, Education and Sport [216-0000000-3348]
- City of Split grant
- Pratt Foundation
- Australian Research Council [FT100100764]
- National Health and Medical Research Council (NHMRC) [APP1032364]
- Medical Research Council [MC_PC_12001/1] Funding Source: researchfish
- Australian Research Council [FT100100764] Funding Source: Australian Research Council
- Swiss National Science Foundation (SNF) [31003A_141197] Funding Source: Swiss National Science Foundation (SNF)
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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.
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