A germline polymorphism of thymine DNA glycosylase induces genomic instability and cellular transformation.
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.
Department of Genetics, Yale University School of Medicine, New Haven, Connecticut, United States of America.
Ashley
A
Sjolund
Department of Therapeutic Radiology, Yale University School of Medicine, New Haven, Connecticut, United States of America.
Antonia A
AA
Nemec
Department of Molecular Biophysics and Biochemistry, Yale University School of Medicine, New Haven, Connecticut, United States of America.
Nicolas
N
Paquet
Department of Microbiology and Molecular Genetics, University of Vermont, Burlington, Vermont, United States of America.
Aishwarya
A
Prakash
Department of Molecular Biophysics and Biochemistry, Yale University School of Medicine, New Haven, Connecticut, United States of America.
Patrick
P
Sung
Department of Microbiology and Molecular Genetics, University of Vermont, Burlington, Vermont, United States of America.
Sylvie
S
Doublié
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; Department of Microbiology and Molecular Genetics, University of Vermont, Burlington, Vermont, United States of America.
Joann B
JB
Sweasy
D020134:Catalytic Domain / Q000235:genetics; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D004260:DNA Repair / Q000235:genetics; D042822:Genomic Instability / Q000235:genetics*; D005854:Germ Cells; D006801:Humans; D020641:Polymorphism, Single Nucleotide; D013329:Structure-Activity Relationship; D013379:Substrate Specificity; D044502:Thymine DNA Glycosylase / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism
D044502:Thymine DNA Glycosylase