Colon cancer-associated DNA polymerase β variant induces genomic instability and cellular transformation.

The Journal of Biological Chemistry
Antonia A NemecJoann B Sweasy

Abstract

Rapidly advancing technology has resulted in the generation of the genomic sequences of several human tumors. We have identified several mutations of the DNA polymerase β (pol β) gene in human colorectal cancer. We have demonstrated that the expression of the pol β G231D variant increased chromosomal aberrations and induced cellular transformation. The transformed phenotype persisted in the cells even once the expression of G231D was extinguished, suggesting that it resulted as a consequence of genomic instability. Biochemical analysis revealed that its catalytic rate was 140-fold slower than WT pol β, and this was a result of the decreased binding affinity of nucleotides by G231D. Residue 231 of pol β lies in close proximity to the template strand of the DNA. Molecular modeling demonstrated that the change from a small and nonpolar glycine to a negatively charged aspartate resulted in a repulsion between the template and residue 231 leading to the distortion of the dNTP binding pocket. In addition, expression of G231D was insufficient to rescue pol β-deficient cells treated with chemotherapeutic agents suggesting that these agents may be effectively used to treat tumors harboring this mutation. More importantly, this suggests ...Continue Reading

References

May 1, 1978·Journal of Virology·D R LowyE M Scolnick
Jun 17, 1998·The Journal of Biological Chemistry·R PrasadS H Wilson
Jun 17, 1998·Proceedings of the National Academy of Sciences of the United States of America·J G HermanS B Baylin
Aug 8, 1998·The Journal of Biological Chemistry·D K SrivastavaS H Wilson
May 18, 1999·The Journal of Biological Chemistry·P FortiniE Dogliotti
Apr 13, 2004·Proceedings of the National Academy of Sciences of the United States of America·Tieming LangJoann B Sweasy
Jul 21, 2004·Molecular Cell·Lee WiederholdTapas K Hazra
Dec 1, 2004·Annual Review of Genetics·Deborah E Barnes, Tomas Lindahl
Sep 24, 2005·Proceedings of the National Academy of Sciences of the United States of America·Joann B SweasyShibani Dalal
Nov 28, 2007·Nucleic Acids Research·Shibani DalalJoann B Sweasy
Jul 24, 2010·Antioxidants & Redox Signaling·David SvilarRobert W Sobol
Apr 2, 2011·Journal of the American Chemical Society·Drew L MurphyJoann B Sweasy
Dec 16, 2011·Nucleic Acids Research·Thomas W KirbyRobert E London
May 12, 2012·The Journal of Biological Chemistry·Katherine A DoniganJoann B Sweasy

❮ Previous
Next ❯

Citations

May 12, 2012·The Journal of Biological Chemistry·Katherine A DoniganJoann B Sweasy
Jun 14, 2013·Nucleic Acids Research·Anbarasi KothandapaniSteve M Patrick
Sep 30, 2014·Nucleic Acids Research·Benjamin A KeenAidan J Doherty
Apr 11, 2014·Biochemistry·William A Beard, Samuel H Wilson
Feb 13, 2014·Journal of the American Chemical Society·Dumitru ArianMarc M Greenberg
Dec 1, 2012·Mutation Research·Ashley B SjolundJoann B Sweasy
Oct 28, 2019·Mutagenesis·Roberto Silvestri, Stefano Landi
Aug 6, 2013·Environmental and Molecular Mutagenesis·Parvathi CharyR Stephen Lloyd
Jan 12, 2017·Molecular Cancer Research : MCR·Antonia A NemecJoann B Sweasy

❮ Previous
Next ❯

Related Concepts

Related Feeds

ASBMB Publications

The American Society for Biochemistry and Molecular Biology (ASBMB) includes the Journal of Biological Chemistry, Molecular & Cellular Proteomics, and the Journal of Lipid Research. Discover the latest research from ASBMB here.

Cancer Genomics (Keystone)

Cancer genomics approaches employ high-throughput technologies to identify the complete catalog of somatic alterations that characterize the genome, transcriptome and epigenome of cohorts of tumor samples. Discover the latest research using such technologies in this feed.