Mutations in SPRTN cause early onset hepatocellular carcinoma, genomic instability and progeroid features.
Mutations in SPRTN cause early onset hepatocellular carcinoma, genomic instability and progeroid features.
复制标题
DOI：
10.1038/ng.3103
复制
发表时间：
2014-11
期刊：
影响因子：
30.8
通讯作者：
Kubisch, Christian
中科院分区：
文献类型：
--
作者：
Lessel, Davor;Vaz, Bruno;Halder, Swagata;Lockhart, Paul J.;Marinovic-Terzic, Ivana;Lopez-Mosqueda, Jaime;Philipp, Melanie;Sim, Joe C. H.;Smith, Katherine R.;Oehler, Judith;Cabrera, Elisa;Freire, Raimundo;Pope, Kate;Nahid, Amsha;Norris, Fiona;Leventer, Richard J.;Delatycki, Martin B.;Barbi, Gotthold;von Ameln, Simon;Hoegel, Josef;Degoricija, Marina;Fertig, Regina;Burkhalter, Martin D.;Hofmann, Kay;Thiele, Holger;Altmueller, Janine;Nuernberg, Gudrun;Nuernberg, Peter;Bahlo, Melanie;Martin, George M.;Aalfs, Cora M.;Oshima, Junko;Terzic, Janos;Amor, David J.;Dikic, Ivan;Ramadan, Kristijan;Kubisch, Christian
与糖尿病有关的退行性和恶性疾病是卫生保健系统面临的主要挑战。因此，阐明致癌和年龄相关的病理学的分子机制越来越具有生物医学意义。我们在来自两个不相关家族的三名患者中发现了SPRTN（也称为C1 orf 124或DVC 1）的双等位基因种系突变。这三名患者都患有一种新的节段性早老综合征，其特征是基因组不稳定和对早发性肝细胞癌的易感性。SPRTN最近被提出在跨损伤DNA合成和防止突变中具有功能。我们在体内和体外鉴定的突变特征已经发现了一个重要的作用，SPRTN在预防DNA复制压力在一般的DNA复制和复制相关的G2/M-检查点调节。除了证明SPRTN突变的致病性外，我们的研究结果还提供了SPRTN功能障碍如何导致加速衰老和癌症易感性的分子解释。
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.
登录
查看更多内容
影响因子：
3.7
作者：
Vaz B;Halder S;Ramadan K
通讯作者：
Ramadan K
影响因子：
14.9
作者：
Kim MS;Machida Y;Vashisht AA;Wohlschlegel JA;Pang YP;Machida YJ
通讯作者：
Machida YJ
影响因子：
16.8
作者：
Davies, Sally L.;North, Phillip S.;Hickson, Ian D.
通讯作者：
Hickson, Ian D.
影响因子：
168.9
作者：
Chen, LS;Lee, L;Oshima, J
通讯作者：
Oshima, J
影响因子：
16
作者：
Centore, Richard C.;Yazinski, Stephanie A.;Tse, Alice;Zou, Lee
通讯作者：
Zou, Lee