ALKBH7 Variant Related to Prostate Cancer Exhibits Altered Substrate Binding.

• Main Authors: Alice R Walker, Pavel Silvestrov, Tina A Müller, Robert H Podolsky, Gregory Dyson, Robert P Hausinger, Gerardo Andrés Cisneros
• Format: Article
• Language: English
• Published: Public Library of Science (PLoS) 2017-02-01
• Series: PLoS Computational Biology
• Online Access: https://doi.org/10.1371/journal.pcbi.1005345

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.