Functional Analysis of RAD51B and RAD23B SNPs using Circular Chromosome Conformation Capture (4C) in Human Prostate Cell Lines
Poster Nov 02, 2016
C. Cieza-Borrella1, S. Wakerell1 , Q. Karlsson1 , R.A. Eeles1,2, Z. Kote-Jarai1
Prostate Cancer (PrCa) is the most frequently diagnosed cancer among men in developed countries and one of the most heritable solid tumours with 58% of cases estimated to be due to genetic factors. The effectiveness of PSA screening remains controversial and new molecular biomarkers are needed to improve application of treatment.
Findings have led to a mixed model of common and rare variants, with variable effect sizes, to explain PrCa genetic origin. Rare mutations in BRCA2 and BRCA1 give rise to moderately elevated risk, whereas Genome-wide Association Studies (GWAS) have identified over 100 common, low penetrance PrCa susceptibility variants, some near or within RAD51B and RAD23B DNA repair genes 1,2,3
RAD51B is a member of the RAD51 protein family with a relevant role in the homologous recombination repair (HRR) pathway of double stranded DNA breaks. Its overexpression has been found to cause cell cycle delay and apoptosis. Variations in the gene sequence have been associated with breast, ovarian, endometrial, colorectal, head and neck cancer and acute leukaemia. RAD23B is involved in the nucleotide excision repair (NER) system and although its role is still not fully understood, polymorphisms in this gene have been associated with breast cancer susceptibility.
Chromatin is highly organised in topologically associating domains (TADs) comprising 100kb to 1Mb clusters of locally interacting DNA regions. The intra- and inter- dynamic of these domains allows the interaction of different regions involving regulatory elements such as promoters, enhancers and silencers, which consequently leads to the regulation of gene expression and recombination4
Genome-wide association studies (GWAS) have identified more than 100 genetic loci associated with type 2 diabetes. The majority of these are located in the intergenic or intragenic regions suggesting that the implicated variants may alter chromatin conformation. This, in turn, is likely to influence the expression of nearby or more remotely located genes to alter beta cell function. At present, however, detailed molecular and functional analyses are still lacking for most of these variants. We recently analysed one of these loci and mapped five causal variants in an islet-specific enhancer cluster within the STARD10 gene locus. Here, we aimed to understand how these causal variants influence b-cell function by alteration of the chromatin structure of enhancer clusterREAD MORE
The nuclear receptors pregnane X receptor (PXR) and constitutive androstane receptor (CAR) are closely related transcription factors that regulate the expression of phase I (cytochrome P450s), phase II metabolizing enzymes and transporter genes in response to xenobiotics, including prescription drugs.READ MORE