Involvement of MRE11A and XPA gene polymorphisms in the modulation of DNA double-strand break repair activity: A genotype–phenotype correlation study

• Published in: DNA repair Vol. 10; no. 10; pp. 1044 - 1050
• Main Authors: Ricceri, Fulvio, Porcedda, Paola, Allione, Alessandra, Turinetto, Valentina, Polidoro, Silvia, Guarrera, Simonetta, Rosa, Fabio, Voglino, Floriana, Pezzotti, Annamaria, Minieri, Valentina, Accomasso, Lisa, Rocchietti, Elisa Cibrario, Orlando, Luca, Giachino, Claudia, Matullo, Giuseppe
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier B.V 10.10.2011; Elsevier
• Subjects: Adult; Alleles; Bacteriology; Biological and medical sciences; DNA Breaks, Double-Stranded; DNA repair; DNA Repair - genetics; DNA-Binding Proteins - genetics; DNA-Binding Proteins - metabolism; Double-strand break repair; Female; Fundamental and applied biological sciences. Psychology; Genetic Association Studies; Growth, nutrition, cell differenciation; H2AX phosphorylation; Haplotypes; Histones - chemistry; Humans; Male; Microbiology; Middle Aged; Molecular and cellular biology; Molecular genetics; MRE11 Homologue Protein; MRE11A; Mutagenesis. Repair; Phosphorylation; Polymorphism, Single Nucleotide - genetics; Radiation, Ionizing; Xeroderma Pigmentosum Group A Protein - genetics; XPA; H2AX phosphorylation; XPA; IR; MRE11A; Double-strand break repair; PBMC; DNA repair; MRN complex; DSB; ICL; MAF; SNP; LD; NER; DSBR; Correlation; Phosphorylation; Genotype; Double strand break; Double stranded DNA; Phenotype; Gene; Repair; Polymorphism
• ISSN: 1568-7864; 1568-7856; 1568-7856
• DOI: 10.1016/j.dnarep.2011.08.003

► We analyzed 768 SNPs in DNA repair genes and H2AX phosphorylation levels. ► We found an association between SNPs in MRE11A and XPA with DSBR activity. ► We suggested that DSBR requires both DSBR and non-DSBR systems. ► Further functional experiments to better investigate DNA repair interplays are needed. DNA double-strand breaks (DSB) are the most lethal form of ionizing radiation-induced DNA damage, and failure to repair them results in cell death. In order to see if any associations exist between DNA repair gene polymorphisms and phenotypic profiles of DSB repair (DSBR) we performed a genotype–phenotype correlation study in 118 young healthy subjects (mean age 25.8 ± 6.7 years). Subjects were genotyped for 768 single nucleotide polymorphisms (SNPs) with a custom Illumina Golden Gate Assay, and an H2AX histone phosphorylation assay was done to test DSBR capacity. We found that H2AX phosphorylation at 1 h was significantly lower in subjects heterozygous (no variant homozygotes were observed) for the XPA gene SNP rs3176683 ( p-value = 0.005), while dephosphorylation was significantly higher in subjects carrying the variant allele in three MRE11A gene SNPs: rs1014666, rs476137 and rs2508784 ( p-value = 0.003, 0.003 and 0.008, respectively). An additive effect of low-activity DNA repair alleles was associated with altered DSBR activity, as demonstrated by both H2AX phosphorylation at 1 h ( p-trend <0.0001) and γH2AX dephosphorylation at 3 h ( p-trend <0.0001). Our study revealed that in addition to SNPs of genes that are well-established players in DSBR, non-DSBR genes, such as the XPA gene that is mainly involved in the nucleotide excision repair pathway, can also influence DSBR in healthy subjects. This suggests that successful DSBR may require both DSBR and non-DSBR mechanisms.