Structural insights into the ligand-binding hot spots of APEX1: an in silico analysis
MEDICINAL CHEMISTRY RESEARCH
Authors: Balasubramanian, Pavithra K.; Balupuri, Anand; Cho, Seung Joo
Abstract
Human apurinic/apyrimidinic endonuclease (APEX1) is a multifunctional protein involved in the repair of DNA damage. It plays a vital role in the base excision repair. Overexpression of APEX1 is observed in a variety of cancers. High APEX1 expression has been associated with deprived result to radio and chemotherapy. It also plays an important role in therapeutic agent resistance and disease suppression. If APEX1 activities could be regulated, the protein would be a favorable and efficient cancer target. So far, inhibitor binding site of APEX1 is not studied in detail. The present study focuses on the identification of ligand-binding hot spot residues of APEX1. Docking studies were performed on seventy-one recently reported APEX1 inhibitors. The docking results identified that most of the compounds with biphenyl moiety occupied the same binding site. Majority of compounds were found to form hydrogen bond interaction with Asn174, Arg156, His309, Tyr128, Asn212, Arg181 and Asn226 and hydrophobic interaction with Phe266, Trp280 and Tyr128. The results could provide useful structural insights about the binding mode of APEX1 inhibitors and the crucial hot spot residues which are essential for ligand recognition.
Association of polymorphisms in base excision repair genes with the risk of breast cancer: A case-control study in north Indian women
ONCOLOGY RESEARCH
Authors: Mitra, Amit Kumar; Singh, Neetu; Singh, Ashok; Garg, Vivek Kumar; Agarwal, Amit; Sharma, Mandira; Chaturvedi, Rashmi; Rath, Srikanta Kumar
Abstract
Inheritance of common genetic variants at one or more base excision repair (BER) genes may result in a reduced DNA repair capacity and in an increased risk of cancers like breast cancer. The present case-control study with 390 north Indian women (155 breast cancer cases and 235 controls) was aimed to investigate the association of seven nonsynonymous BER gene polymorphisms viz. rs1130409/T1865G (APEX1), rs1799782/T22142C (XRCC1), rs25487/G23990A (XRCC1), rs4989588/T3337A (FEN1), rs4989586/G3259A (FEN1), rs4989587/C3315T (FEN1), and rs1050525/G6941T (PCNA) with breast cancer susceptibility. Statistically significant association with breast cancer risk was observed for rs1130409 homozygous mutant GG [odds ratio (OR) 3.35, 95% confidence interval (CI) 1.36-8.26), heterozygous GT (OR 2.42, 95% Cl 1.56-3.76), and combined mutant (GT + GG) (OR 2.52, 95% CI 1.65-3.86] genotypes and rs25487 homozygous mutant AA (OR 2.91, 95% CI 1.66-5.10) and combined mutant (AA + AG) (OR 1.41, 95% CI 0.903-2.19) genotypes, whereas protective association was exhibited by rs1799782 homozygous mutant CC (OR 0.413, 95% CI 0.082-2.08), heterozygous TC (OR 0.351, 95% CI 0.189-0.650), and combined mutant (TC + CC) (OR 0.357, 95% CI 0.199-0.641) genotypes. Association study using reconstructed haplo-types of XRCC1 gene showed positive association for the TA haplotype (OR 2.014, 95% CI 1.462-2.775) and a protective association for the CG haplotype (OR 0.173, 95% CI 0.052-0.576) pertaining to breast cancer risk. The results indicate that the polymorphisms rs1130409 (APEX1) and rs25487 (XRCC1) might be involved in contributing towards breast cancer susceptibility, while rs1799782 (XRCC1) might have protective influence.