Sjolund Ashley, Nemec Antonia A, Paquet Nicolas, Prakash Aishwarya, Sung Patrick, Doublié Sylvie, Sweasy Joann B
Department of Genetics, Yale University School of Medicine, New Haven, Connecticut, United States of America.
Department of Therapeutic Radiology, Yale University School of Medicine, New Haven, Connecticut, United States of America.
PLoS Genet. 2014 Nov 6;10(11):e1004753. doi: 10.1371/journal.pgen.1004753. eCollection 2014 Nov.
Thymine DNA glycosylase (TDG) functions in base excision repair, a DNA repair pathway that acts in a lesion-specific manner to correct individual damaged or altered bases. TDG preferentially catalyzes the removal of thymine and uracil paired with guanine, and is also active on 5-fluorouracil (5-FU) paired with adenine or guanine. The rs4135113 single nucleotide polymorphism (SNP) of TDG is found in 10% of the global population. This coding SNP results in the alteration of Gly199 to Ser. Gly199 is part of a loop responsible for stabilizing the flipped abasic nucleotide in the active site pocket. Biochemical analyses indicate that G199S exhibits tighter binding to both its substrate and abasic product. The persistent accumulation of abasic sites in cells expressing G199S leads to the induction of double-strand breaks (DSBs). Cells expressing the G199S variant also activate a DNA damage response. When expressed in cells, G199S induces genomic instability and cellular transformation. Together, these results suggest that individuals harboring the G199S variant may have increased risk for developing cancer.
胸腺嘧啶DNA糖基化酶（TDG）在碱基切除修复中发挥作用，碱基切除修复是一种DNA修复途径，以损伤特异性方式作用于纠正单个受损或改变的碱基。TDG优先催化与鸟嘌呤配对的胸腺嘧啶和尿嘧啶的去除，并且对与腺嘌呤或鸟嘌呤配对的5-氟尿嘧啶（5-FU）也有活性。TDG的rs4135113单核苷酸多态性（SNP）在全球10%的人口中被发现。这种编码SNP导致甘氨酸199变为丝氨酸。甘氨酸199是负责稳定活性位点口袋中翻转的无碱基核苷酸的环的一部分。生化分析表明，G199S对其底物和无碱基产物都表现出更强的结合。在表达G199S的细胞中无碱基位点的持续积累导致双链断裂（DSB）的诱导。表达G199S变体的细胞也会激活DNA损伤反应。当在细胞中表达时，G199S会诱导基因组不稳定和细胞转化。总之，这些结果表明携带G199S变体的个体患癌症的风险可能增加。
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