A Germline Polymorphism of Thymine DNA Glycosylase Induces Genomic Instability and Cellular Transformation

English version České info

DNA repair is vital to the survival and propagation of cells. It helps protect DNA from becoming permanently damaged and prevents cells from becoming cancerous. The base excision repair (BER) pathway is responsible for the removal of up to 20,000 lesions/cell/day. Thymine DNA glycosylase (TDG) is one of the DNA glycosylases that initiates BER. There is a germline variant of TDG that is found in 10% of the global population, where amino acid residue glycine 199 is mutated to serine. Here, we provide evidence that TDG variant G199S binds significantly more tightly to its abasic product and leads to increased DNA strand breaks in cells. We go on to show that G199S induces genomic instability, in the form of chromosomal aberrations, and leads to cellular transformation, both hallmarks of tumorigenesis. Collectively, our work suggests that a germline variant of TDG can drive carcinogenesis.

Vyšlo v časopise: A Germline Polymorphism of Thymine DNA Glycosylase Induces Genomic Instability and Cellular Transformation. PLoS Genet 10(11): e32767. doi:10.1371/journal.pgen.1004753
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1004753

Souhrn

Zdroje

1. BarnesDE, LindahlT (2004) Repair and genetic consequences of endogenous DNA base damage in mammalian cells. Annu Rev Genet 38: 445–476.

2. NeddermannP, JiricnyJ (1993) The purification of a mismatch-specific thymine-DNA glycosylase from HeLa cells. J Biol Chem 268: 21218–21224.

3. HardelandU, BenteleM, JiricnyJ, ScharP (2003) The versatile thymine DNA-glycosylase: a comparative characterization of the human, Drosophila and fission yeast orthologs. Nucleic Acids Res 31: 2261–2271.

4. MorganMT, BennettMT, DrohatAC (2007) Excision of 5-halogenated uracils by human thymine DNA glycosylase. Robust activity for DNA contexts other than CpG. J Biol Chem 282: 27578–27586.

5. CortazarD, KunzC, SaitoY, SteinacherR, ScharP (2007) The enigmatic thymine DNA glycosylase. DNA Repair (Amst) 6: 489–504.

6. HeYF, LiBZ, LiZ, LiuP, WangY, et al. (2011) Tet-mediated formation of 5-carboxylcytosine and its excision by TDG in mammalian DNA. Science 333: 1303–1307.

7. MaitiA, DrohatAC (2011) Thymine DNA glycosylase can rapidly excise 5-formylcytosine and 5-carboxylcytosine: potential implications for active demethylation of CpG sites. J Biol Chem 286: 35334–35338.

8. NabelCS, JiaH, YeY, ShenL, GoldschmidtHL, et al. (2012) AID/APOBEC deaminases disfavor modified cytosines implicated in DNA demethylation. Nat Chem Biol 8: 751–758.

9. HashimotoH, HongS, BhagwatAS, ZhangX, ChengX (2012) Excision of 5-hydroxymethyluracil and 5-carboxylcytosine by the thymine DNA glycosylase domain: its structural basis and implications for active DNA demethylation. Nucleic Acids Res 40: 10203–10214.

10. MaitiA, MorganMT, PozharskiE, DrohatAC (2008) Crystal structure of human thymine DNA glycosylase bound to DNA elucidates sequence-specific mismatch recognition. Proceedings of the National Academy of Sciences of the United States of America 105: 8890–8895.

11. Wen-BinM, WeiW, Yu-LanQ, FangJ, Zhao-LinX (2009) Micronucleus occurrence related to base excision repair gene polymorphisms in Chinese workers occupationally exposed to vinyl chloride monomer. J Occup Environ Med 51: 578–585.

12. LiW-Q, HuN, HylandPL, GaoY, WangZ-M, et al. (2013) Genetic variants in DNA repair pathway genes and risk of esophageal squamous cell carcinoma and gastric adenocarcinoma in a Chinese population. Carcinogenesis 34: 1536–1542.

13. KrzesniakM, ButkiewiczD, SamojednyA, ChorazyM, RusinM (2004) Polymorphisms in TDG and MGMT genes - epidemiological and functional study in lung cancer patients from Poland. Ann Hum Genet 68: 300–312.

14. CurtinK, UlrichCM, SamowitzWS, WolffRK, DugganDJ, et al. (2011) Candidate pathway polymorphisms in one-carbon metabolism and risk of rectal tumor mutations. Int J Mol Epidemiol Genet 2: 1–8.

15. XuX, YuT, ShiJ, ChenX, ZhangW, et al. (2014) Thymine DNA Glycosylase is a Positive Regulator of Wnt Signaling in Colorectal Cancer. J Biol Chem 289: 8881–90.

16. MaitiA, MorganMT, PozharskiE, DrohatAC (2008) Crystal structure of human thymine DNA glycosylase bound to DNA elucidates sequence-specific mismatch recognition. Proc Natl Acad Sci U S A 105: 8890–8895.

17. KunzC, FockeF, SaitoY, SchuermannD, LettieriT, et al. (2009) Base excision by thymine DNA glycosylase mediates DNA-directed cytotoxicity of 5-fluorouracil. PLoS Biol 7: e91.

18. RobinsonHMR, JonesR, WalkerM, ZachosG, BrownR, et al. (2006) Chk1-dependent slowing of S-phase progression protects DT40 B-lymphoma cells against killing by the nucleoside analogue 5-fluorouracil. Oncogene 25: 5359–5369.

19. XiaoZ, XueJ, SowinTJ, RosenbergSH, ZhangH (2004) A novel mechanism of checkpoint abrogation conferred by Chk1 downregulation. Oncogene 24: 1403–1411.

20. LiuQ, GuntukuS, CuiXS, MatsuokaS, CortezD, et al. (2000) Chk1 is an essential kinase that is regulated by Atr and required for the G(2)/M DNA damage checkpoint. Genes Dev 14: 1448–1459.

21. GalickHA, KatheS, LiuM, Robey-BondS, KidaneD, et al. (2013) Germ-line variant of human NTH1 DNA glycosylase induces genomic instability and cellular transformation. Proc Natl Acad Sci U S A 110: 14314–14319.

22. YamtichJ, NemecAA, KehA, SweasyJB (2012) A germline polymorphism of DNA polymerase beta induces genomic instability and cellular transformation. PLoS Genet 8: e1003052.

23. NemecAA, DoniganKA, MurphyDL, JaegerJ, SweasyJB (2012) Colon cancer-associated DNA polymerase beta variant induces genomic instability and cellular transformation. J Biol Chem 287: 23840–23849.

24. NemecAA, MurphyDL, DoniganKA, SweasyJB (2014) The S229L Colon Tumor-Associated Variant of DNA Polymerase Beta Induces Cellular Transformation As A Result Of Decreased Polymerization Efficiency. J Biol Chem 289: 13708–16.

25. HoDH, PazdurR, CovingtonW, BrownN, HuoYY, et al. (1998) Comparison of 5-fluorouracil pharmacokinetics in patients receiving continuous 5-fluorouracil infusion and oral uracil plus N1-(2′-tetrahydrofuryl)-5-fluorouracil. Clin Cancer Res 4: 2085–2088.

26. JouliaJM, PinguetF, YchouM, DuffourJ, AstreC, et al. (1999) Plasma and salivary pharmacokinetics of 5-fluorouracil (5-FU) in patients with metastatic colorectal cancer receiving 5-FU bolus plus continuous infusion with high-dose folinic acid. Eur J Cancer 35: 296–301.

27. JouliaJM, PinguetF, YchouM, DuffourJ, TopartD, et al. (1997) Pharmacokinetics of 5-fluorouracil (5-FUra) in patients with metastatic colorectal cancer receiving 5-FUra bolus plus continuous infusion with high dose folinic acid (LV5FU2). Anticancer Res 17: 2727–2730.

28. KoningsIR, SleijferS, MathijssenRH, de BruijnP, Ghobadi Moghaddam-HelmantelIM, et al. (2011) Increasing tumoral 5-fluorouracil concentrations during a 5-day continuous infusion: a microdialysis study. Cancer Chemother Pharmacol 67: 1055–1062.

29. AdjeiAA, ReidJM, DiasioRB, SloanJA, SmithDA, et al. (2002) Comparative pharmacokinetic study of continuous venous infusion fluorouracil and oral fluorouracil with eniluracil in patients with advanced solid tumors. J Clin Oncol 20: 1683–1691.

30. Smet-NoccaC, WieruszeskiJM, LegerH, EilebrechtS, BeneckeA (2011) SUMO-1 regulates the conformational dynamics of thymine-DNA Glycosylase regulatory domain and competes with its DNA binding activity. BMC Biochem 12: 4.

31. HardelandU, SteinacherR, JiricnyJ, ScharP (2002) Modification of the human thymine-DNA glycosylase by ubiquitin-like proteins facilitates enzymatic turnover. Embo J 21: 1456–1464.

32. BarrettTE, ScharerOD, SavvaR, BrownT, JiricnyJ, et al. (1999) Crystal structure of a thwarted mismatch glycosylase DNA repair complex. Embo J 18: 6599–6609.

33. MorganMT, MaitiA, FitzgeraldME, DrohatAC (2011) Stoichiometry and affinity for thymine DNA glycosylase binding to specific and nonspecific DNA. Nucleic Acids Res 39: 2319–2329.