title: Involvement of MRE11A and XPA gene polymorphisms in the modulation of DNA double-strand break repair activity: a genotype-phenotype correlation study.
abstract: 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±6.7years). 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 1h 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 3h (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.
authors: Human Genetics Foundation-HuGeF, Turin, Italy.
authors: Fulvio
authors: F
authors: Ricceri
authors: Paola
authors: P
authors: Porcedda
authors: Alessandra
authors: A
authors: Allione
authors: Valentina
authors: V
authors: Turinetto
authors: Silvia
authors: S
authors: Polidoro
authors: Simonetta
authors: S
authors: Guarrera
authors: Fabio
authors: F
authors: Rosa
authors: Floriana
authors: F
authors: Voglino
authors: Annamaria
authors: A
authors: Pezzotti
authors: Valentina
authors: V
authors: Minieri
authors: Lisa
authors: L
authors: Accomasso
authors: Elisa
authors: E
authors: Cibrario Rocchietti
authors: Luca
authors: L
authors: Orlando
authors: Claudia
authors: C
authors: Giachino
authors: Giuseppe
authors: G
authors: Matullo
mesh_terms: D000328:Adult; D000483:Alleles; D053903:DNA Breaks, Double-Stranded; D004260:DNA Repair / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D005260:Female; D056726:Genetic Association Studies; D006239:Haplotypes; D006657:Histones / Q000737:chemistry; D006801:Humans; D000076228:MRE11 Homologue Protein; D008297:Male; D008875:Middle Aged; D010766:Phosphorylation; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D011839:Radiation, Ionizing; D051760:Xeroderma Pigmentosum Group A Protein / Q000235:genetics*
chemical_list: D004268:DNA-Binding Proteins; C468783:H2AX protein, human; D006657:Histones; C121766:MRE11 protein, human; C497314:XPA protein, human; D051760:Xeroderma Pigmentosum Group A Protein; D000076228:MRE11 Homologue Protein