ALKBH7 Variant Related to Prostate Cancer Exhibits Altered Substrate Binding.
Alice R WalkerPavel SilvestrovTina A MüllerRobert H PodolskyGregory DysonRobert P HausingerGerardo Andrés CisnerosPublished in: PLoS computational biology (2017)
The search for prostate cancer biomarkers has received increased attention and several DNA repair related enzymes have been linked to this dysfunction. Here we report a targeted search for single nucleotide polymorphisms (SNPs) and functional impact characterization of human ALKBH family dioxygenases related to prostate cancer. Our results uncovered a SNP of ALKBH7, rs7540, which is associated with prostate cancer disease in a statistically significantly manner in two separate cohorts, and maintained in African American men. Comparisons of molecular dynamics (MD) simulations on the wild-type and variant protein structures indicate that the resulting alteration in the enzyme induces a significant structural change that reduces ALKBH7's ability to bind its cosubstrate. Experimental spectroscopy studies with purified proteins validate our MD predictions and corroborate the conclusion that this cancer-associated mutation affects productive cosubstrate binding in ALKBH7.
Keyphrases
- prostate cancer
- molecular dynamics
- radical prostatectomy
- dna repair
- african american
- density functional theory
- high resolution
- wild type
- dna damage
- endothelial cells
- genome wide
- binding protein
- oxidative stress
- dna binding
- dna damage response
- small molecule
- cancer therapy
- single molecule
- gene expression
- dna methylation
- induced pluripotent stem cells