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ERCC2/XPD Lys751Gln alter DNA repair efficiency of platinum-induced DNA damage through P53 pathway

Guopei Zhang1, Yangyang Guan1, Yuejiao Zhao2

  • 1Dept. of Toxicology, School of Public Health, China Medical University, Shenyang, PR China.

Chemico-Biological Interactions
|December 29, 2016
PubMed

Insights

The ERCC2/XPD Lys751Gln (rs13181) polymorphism affects DNA repair capacity. The AA genotype shows increased viability and reduced DNA damage after cisplatin treatment compared to the CC genotype, suggesting a role in platinum resistance.

Area of Science:

  • Molecular Biology
  • Genetics
  • Cancer Research

Background:

  • Platinum-based chemotherapy induces DNA damage, primarily Pt-DNA adducts, leading to cancer cell death.
  • The Nucleotide Excision Repair (NER) system, involving ERCC2/XPD, repairs platinum-induced DNA damage.
  • Single Nucleotide Polymorphisms (SNPs) in ERCC2/XPD are linked to platinum resistance.

Purpose of the Study:

  • To investigate the causal relationship between the ERCC2/XPD Lys751Gln (rs13181) polymorphism and DNA repair capacity for platinum-induced DNA damage.
  • To elucidate the functional impact of different ERCC2/XPD rs13181 genotypes on cellular response to cisplatin.

Main Methods:

  • Transfection of ERCC2/XPD deficient CHO cells (UV5) with cDNA clones expressing different rs13181 genotypes (AA and CC).
  • Treatment of transfected cells with cisplatin.
  • Assessment of cellular viability (MTT assay), DNA damage (comet assay, RAD51 staining), cell cycle distribution, apoptosis rates (FCM), and P53 mRNA/protein levels.

Main Results:

  • UV5 cells expressing ERCC2 (AA) genotype exhibited significantly higher viability and reduced DNA damage levels compared to UV5 cells expressing ERCC2 (CC) genotype after cisplatin treatment.
  • The ERCC2 rs13181 AA to CC genotype mutation was associated with prolonged S phase in the cell cycle.
  • Apoptosis was alleviated in UV5ERCC2 (AA) cells, correlating with lower P53 mRNA levels and prolonged phospho-P53 expression.

Conclusions:

  • The ERCC2/XPD rs13181 polymorphism is functionally linked to DNA repair capacity of platinum-induced DNA damage.
  • This polymorphism may influence cisplatin resistance by modulating DNA repair efficiency, cell cycle progression, and apoptosis.
  • Findings provide insights into the relationship between cisplatin resistance and ERCC2/XPD rs13181 polymorphism.
Keywords:
Cisplatin resistanceDNA repair capacity (DRC)ERCC2/XPDLys751Glnrs13181Nucleotide excision repair (NER)Transfected cell model

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