Mutations of the DNA repair gene PNKP in a patient with microcephaly, seizures, and developmental delay (MCSZ) presenting with a high-grade brain tumor.
Mutations of the DNA repair gene PNKP in a patient with microcephaly, seizures, and developmental delay (MCSZ) presenting with a high-grade brain tumor.
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1例患有高级别脑肿瘤的小头畸形、癫痫发作和发育迟缓（MCSZ）患者的DNA修复基因PNKP突变
DOI：
10.1038/s41598-022-09097-w
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发表时间：
2022-03-30
影响因子：
4.6
通讯作者：
Ene CI
中科院分区：
文献类型：
--
作者：
Jiang B;Murray C;Cole BL;Glover JNM;Chan GK;Deschenes J;Mani RS;Subedi S;Nerva JD;Wang AC;Lockwood CM;Mefford HC;Leary SES;Ojemann JG;Weinfeld M;Ene CI
多核苷酸激酶-磷酸酶（PNKP）是一种双功能酶，具有DNA 3′-磷酸酶和DNA 5′-激酶活性，是处理活性氧（ROS）、电离辐射和拓扑异构酶I中毒产生的单链和双链断裂末端所必需的。尽管PNKP是DNA修复的核心，但目前还没有报道将小头畸形、癫痫和发育迟缓（MSCZ）患者的PNKP突变与癌症联系起来。在这里，我们描述了PNKP基因2种系点突变的生化意义，该突变发生在一名3岁的MSCZ男性患者的小脑内，他表现为高级别脑肿瘤（多形性胶质母细胞瘤）。功能和生化研究表明，这些PNKP突变显著降低了DNA激酶/磷酸酶的活性，改变了其细胞分布，导致DNA单双链断裂修复缺陷，并与更高的致癌转化倾向相关。我们的研究结果表明，特定的PNKP突变可能通过限制DNA损伤修复和增加导致儿童胶质瘤相关驱动突变（如ATRX和TP53）的自发突变率，促进中枢神经系统易感细胞内的肿瘤起始。
Polynucleotide Kinase-Phosphatase (PNKP) is a bifunctional enzyme that possesses both DNA 3′-phosphatase and DNA 5′-kinase activities, which are required for processing termini of single- and double-strand breaks generated by reactive oxygen species (ROS), ionizing radiation and topoisomerase I poisons. Even though PNKP is central to DNA repair, there have been no reports linking PNKP mutations in a Microcephaly, Seizures, and Developmental Delay (MSCZ) patient to cancer. Here, we characterized the biochemical significance of 2 germ-line point mutations in the PNKP gene of a 3-year old male with MSCZ who presented with a high-grade brain tumor (glioblastoma multiforme) within the cerebellum. Functional and biochemical studies demonstrated these PNKP mutations significantly diminished DNA kinase/phosphatase activities, altered its cellular distribution, caused defective repair of DNA single/double stranded breaks, and were associated with a higher propensity for oncogenic transformation. Our findings indicate that specific PNKP mutations may contribute to tumor initiation within susceptible cells in the CNS by limiting DNA damage repair and increasing rates of spontaneous mutations resulting in pediatric glioma associated driver mutations such as ATRX and TP53.
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影响因子：
5.3
作者：
Dumitrache, Lavinia C.;McKinnon, Peter J.
通讯作者：
McKinnon, Peter J.
影响因子：
3.7
作者：
Hu Y;Wang C;Huang K;Xia F;Parvin JD;Mondal N
通讯作者：
Mondal N
影响因子：
1.9
作者：
Kuo, Ayako J.;Paulson, Vera A.;Lockwood, Christina M.
通讯作者：
Lockwood, Christina M.
影响因子：
9.8
作者：
Bras, Jose;Alonso, Isabel;Guerreiro, Rita
通讯作者：
Guerreiro, Rita
影响因子：
4.8
作者：
Karimi-Busheri, F;Daly, G;Weinfeld, M
通讯作者：
Weinfeld, M