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Abstract
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.
Highlights
Prostate cancer is the 2nd leading cause of death from cancer for men[1]
Improvements in personalized DNA sequencing have led to an increased interest in targeted biomarkers for therapeutic and diagnostic purposes
We report on a new biomarker for prostate cancer found through a targeted search for single nucleotide polymorphisms (SNPs) of the genes encoding human ALKBH family dioxygenases
Summary
Prostate cancer is the 2nd leading cause of death from cancer for men[1]. In 2015 the number of new cases in the USA was estimated at 220,800 and the number of deaths from the disease at 27,540[1]. The decreased cost of DNA sequencing and the growing interest in precision medicine have spurred the accumulation of personalized genomic data [2,3,4,5,6] This development makes it possible to determine mutations of genes that are directly linked to a given phenotype and can aid in the development of novel diagnostic and therapeutic avenues. Cells have a variety of mechanisms to repair damage, and defects in DNA repair and damage response pathways can have deleterious consequences [7] Some of these defects have been directly linked to prostate cancer [8,9]. Some members of the ALKBH family of dioxygenases, named as such because they are homologues of the Escherichia coli AlkB DNA repair enzyme, catalyze the oxidation of the alkyl moiety on damaged bases to directly repair the lesion. Alkyl lesions can be repaired by specific methyltransferases, but this reaction inactivates the single-use enzyme [11]
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