斯巴达缺陷导致拓扑异构酶1切割复合物的积累和肿瘤发生。
Spartan deficiency causes accumulation of Topoisomerase 1 cleavage complexes and tumorigenesis.
作者信息
Maskey Reeja S, Flatten Karen S, Sieben Cynthia J, Peterson Kevin L, Baker Darren J, Nam Hyun-Ja, Kim Myoung Shin, Smyrk Thomas C, Kojima Yusuke, Machida Yuka, Santiago Annyoceli, van Deursen Jan M, Kaufmann Scott H, Machida Yuichi J
机构信息
Department of Oncology, Mayo Clinic, 200 First St. SW, Rochester, MN 55905, USA.
Department of Biochemistry and Molecular Biology, Mayo Clinic, 200 First St. SW, Rochester, MN 55905, USA.
出版信息
Nucleic Acids Res. 2017 May 5;45(8):4564-4576. doi: 10.1093/nar/gkx107.
Germline mutations in SPRTN cause Ruijs-Aalfs syndrome (RJALS), a disorder characterized by genome instability, progeria and early onset hepatocellular carcinoma. Spartan, the protein encoded by SPRTN, is a nuclear metalloprotease that is involved in the repair of DNA-protein crosslinks (DPCs). Although Sprtn hypomorphic mice recapitulate key progeroid phenotypes of RJALS, whether this model expressing low amounts of Spartan is prone to DPC repair defects and spontaneous tumors is unknown. Here, we showed that the livers of Sprtn hypomorphic mice accumulate DPCs containing Topoisomerase 1 covalently linked to DNA. Furthermore, these mice exhibited DNA damage, aneuploidy and spontaneous tumorigenesis in the liver. Collectively, these findings provide evidence that partial loss of Spartan impairs DPC repair and tumor suppression.
SPRTN基因的种系突变会导致鲁伊斯-阿尔夫斯综合征（RJALS），这是一种以基因组不稳定、早衰和早发性肝细胞癌为特征的疾病。Spartan是由SPRTN编码的蛋白质，是一种核金属蛋白酶，参与DNA-蛋白质交联（DPC）的修复。尽管Spartn低表达小鼠重现了RJALS的关键早衰样表型，但这种表达少量Spartan的模型是否易于出现DPC修复缺陷和自发肿瘤尚不清楚。在这里，我们表明Spartn低表达小鼠的肝脏中积累了含有与DNA共价连接的拓扑异构酶1的DPC。此外，这些小鼠在肝脏中表现出DNA损伤、非整倍体和自发肿瘤发生。总的来说，这些发现提供了证据，表明Spartan的部分缺失会损害DPC修复和肿瘤抑制。
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