TITLE

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

AUTHOR(S)
Sjolund, Ashley; Nemec, Antonia A.; Paquet, Nicolas; Prakash, Aishwarya; Sung, Patrick; DoubliƩ, Sylvie; Sweasy, Joann B.
PUB. DATE
November 2014
SOURCE
PLoS Genetics;Nov2014, Vol. 10 Issue 11, p1
SOURCE TYPE
Academic Journal
DOC. TYPE
Article
ABSTRACT
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.
ACCESSION #
83193831

 

Share

Read the Article

Courtesy of THE LIBRARY OF VIRGINIA

Sorry, but this item is not currently available from your library.

Try another library?
Sign out of this library

Other Topics