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

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• 作者：Fulvio Ricceri^a ;   ; ^b ;   ; ¹ ; Paola Porcedda^c ;   ; ^d ;   ; ¹ ; Alessandra Allione^a ;   ; ¹ ; Valentina Turinetto^c ; Silvia Polidoro^a ; Simonetta Guarrera^a ; Fabio Rosa^a ; Floriana Voglino^a ; Annamaria Pezzotti^a ; Valentina Minieri^c ; Lisa Accomasso^c ; Elisa Cibrario Rocchietti^c ; Luca Orlando^c ; Claudia Giachino^c ; Giuseppe Matullo^a ;   ; ^b ;   ; ^{giuseppe.matullo@unito.it}
• 关键词：DNA repair ; Double-strand break repair ; MRE11A ; XPA ; H2AX phosphorylation
• 刊名：DNA Repair
• 出版年：2011
• 出版时间：10 October 2011
• 年：2011
• 卷：10
• 期：10
• 页码：1044-1050
• 全文大小：335 K

文摘

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¨Cphenotype correlation study in 118 young healthy subjects (mean age 25.8 ¡À 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 ¦ÃH2AX 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.