RGD Reference Report - Inter-individual variation in nucleotide excision repair pathway is modulated by non-synonymous polymorphisms in ERCC4 and MBD4 genes. - Rat Genome Database

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Inter-individual variation in nucleotide excision repair pathway is modulated by non-synonymous polymorphisms in ERCC4 and MBD4 genes.

Authors: Allione, A  Guarrera, S  Russo, A  Ricceri, F  Purohit, R  Pagnani, A  Rosa, F  Polidoro, S  Voglino, F  Matullo, G 
Citation: Allione A, etal., Mutat Res. 2013 Nov-Dec;751-752:49-54. doi: 10.1016/j.mrfmmm.2013.08.005. Epub 2013 Sep 1.
RGD ID: 9588971
Pubmed: PMID:24004570   (View Abstract at PubMed)
DOI: DOI:10.1016/j.mrfmmm.2013.08.005   (Journal Full-text)

Inter-individual differences in DNA repair capacity (DRC) may lead to genome instability and, consequently, modulate individual cancer risk. Among the different DNA repair pathways, nucleotide excision repair (NER) is one of the most versatile, as it can eliminate a wide range of helix-distorting DNA lesions caused by ultraviolet light irradiation and chemical mutagens. We performed a genotype-phenotype correlation study in 122 healthy subjects in order to assess if any associations exist between phenotypic profiles of NER and DNA repair gene single nucleotide polymorphisms (SNPs). Individuals were genotyped for 768 SNPs with a custom Illumina Golden Gate Assay, and peripheral blood mononuclear cells (PBMCs) of the same subjects were tested for a NER comet assay to measure DRC after challenging cells by benzo(a)pyrene diolepoxide (BPDE). We observed a large inter-individual variability of NER capacity, with women showing a statistically significant lower DRC (mean +/- SD: 6.68 +/- 4.76; p = 0.004) than men (mean +/- SD: 8.89 +/- 5.20). Moreover, DRC was significantly lower in individuals carrying a variant allele for the ERCC4 rs1800124 non-synonymous SNP (nsSNP) (p = 0.006) and significantly higher in subjects with the variant allele of MBD4 rs2005618 SNP (p = 0.008), in linkage disequilibrium (r(2) = 0.908) with rs10342 nsSNP. Traditional in silico docking approaches on protein-DNA and protein-protein interaction showed that Gly875 variant in ERCC4 (rs1800124) decreases the DNA-protein interaction and that Ser273 and Thr273 variants in MBD4 (rs10342) indicate complete loss of protein-DNA interactions. Our results showed that NER inter-individual capacity can be modulated by cross-talk activity involving nsSNPs in ERCC4 and MBD4 genes, and they suggested to better investigate SNP effect on cancer risk and response to chemo- and radiotherapies.

Molecular Pathway Annotations    Click to see Annotation Detail View

RGD Manual Annotations

TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
altered DNA modification pathway  IMP 9588971in silico assessment of loss of DNA-protein interactions and observed enhancement of DNA repair capacity (DRC) in the context of nucleotide excision repair (NER) pathway for SNPRGD 
altered DNA modification pathway  ISOMBD4 (Homo sapiens)9588971; 9588971in silico assessment of loss of DNA-protein interactions and observed enhancement of DNA repair capacity (DRC) in the context of nucleotide excision repair (NER) pathway for SNPRGD 
altered nucleotide excision repair pathway   IMP 9588971in silico assessment of alteration of DNA-protein and protein-protein interactions and observed reduction of DNA repair capacity in the context of nucleotide excision repair pathway for SNPRGD 
altered nucleotide excision repair pathway   ISOERCC4 (Homo sapiens)9588971; 9588971in silico assessment of alteration of DNA-protein and protein-protein interactions and observed reduction of DNA repair capacity in the context of nucleotide excision repair pathway for SNPRGD 
Objects Annotated

Genes (Rattus norvegicus)
Ercc4  (ERCC excision repair 4, endonuclease catalytic subunit)
Mbd4  (methyl-CpG binding domain 4 DNA glycosylase)

Genes (Mus musculus)
Ercc4  (excision repair cross-complementing rodent repair deficiency, complementation group 4)
Mbd4  (methyl-CpG binding domain protein 4)

Genes (Homo sapiens)
ERCC4  (ERCC excision repair 4, endonuclease catalytic subunit)
MBD4  (methyl-CpG binding domain 4, DNA glycosylase)


Additional Information