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

2.50
Hdl Handle:
http://hdl.handle.net/10146/189941
Title:
Involvement of MRE11A and XPA gene polymorphisms in the modulation of DNA double-strand break repair activity: a genotype-phenotype correlation study.
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
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.
Citation:
DNA Repair (Amst.) 2011, 10 (10):1044-1050
Journal:
DNA Repair
Issue Date:
10-Oct-2011
URI:
http://hdl.handle.net/10146/189941
DOI:
10.1016/j.dnarep.2011.08.003
PubMed ID:
21880556
Additional Links:
http://www.sciencedirect.com/science/article/pii/S1568786411002096
Type:
Article
Language:
en
ISSN:
1568-7856
Sponsors:
This work was supported by grants from the Associazione Italiana per la Ricerca sul Cancro (Italy; G.M., C.G.), the Progetto Integrato Oncologia, Regione Toscana – Ministero della Salute “Identification of population risk profiles as an approach to cancer prevention” and the Environmental Cancer Risk Nutrition and Individual Susceptibility Project (G.M.), a network of excellence operating within the European Union Sixth Framework Program, Priority 5: ‘Food Quality and Safety’ (Contract No. 513943).
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Full metadata record

DC FieldValue Language
dc.contributor.authorRicceri, Fulvioen
dc.contributor.authorPorcedda, Paolaen
dc.contributor.authorAllione, Alessandraen
dc.contributor.authorTurinetto, Valentinaen
dc.contributor.authorPolidoro, Silviaen
dc.contributor.authorGuarrera, Simonettaen
dc.contributor.authorRosa, Fabioen
dc.contributor.authorVoglino, Florianaen
dc.contributor.authorPezzotti, Annamariaen
dc.contributor.authorMinieri, Valentinaen
dc.contributor.authorAccomasso, Lisaen
dc.contributor.authorRocchietti, Elisa Cibrarioen
dc.contributor.authorOrlando, Lucaen
dc.contributor.authorGiachino, Claudiaen
dc.contributor.authorMatullo, Giuseppeen
dc.date.accessioned2011-11-18T12:58:36Z-
dc.date.available2011-11-18T12:58:36Z-
dc.date.issued2011-10-10-
dc.identifier.citationDNA Repair (Amst.) 2011, 10 (10):1044-1050en
dc.identifier.issn1568-7856-
dc.identifier.pmid21880556-
dc.identifier.doi10.1016/j.dnarep.2011.08.003-
dc.identifier.urihttp://hdl.handle.net/10146/189941-
dc.description.abstractDNA 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.en
dc.description.sponsorshipThis work was supported by grants from the Associazione Italiana per la Ricerca sul Cancro (Italy; G.M., C.G.), the Progetto Integrato Oncologia, Regione Toscana – Ministero della Salute “Identification of population risk profiles as an approach to cancer prevention” and the Environmental Cancer Risk Nutrition and Individual Susceptibility Project (G.M.), a network of excellence operating within the European Union Sixth Framework Program, Priority 5: ‘Food Quality and Safety’ (Contract No. 513943).en
dc.language.isoenen
dc.relation.urlhttp://www.sciencedirect.com/science/article/pii/S1568786411002096en
dc.subjectDNA repairen
dc.subjectDouble-strand break repairen
dc.subjectMRE11Aen
dc.subjectXPAen
dc.subjectH2AX phosphorylationen
dc.subject.meshAdult-
dc.subject.meshAlleles-
dc.subject.meshDNA Breaks, Double-Stranded-
dc.subject.meshDNA Repair-
dc.subject.meshDNA-Binding Proteins-
dc.subject.meshFemale-
dc.subject.meshGenetic Association Studies-
dc.subject.meshHaplotypes-
dc.subject.meshHistones-
dc.subject.meshHumans-
dc.subject.meshMale-
dc.subject.meshMiddle Aged-
dc.subject.meshPhosphorylation-
dc.subject.meshPolymorphism, Single Nucleotide-
dc.subject.meshRadiation, Ionizing-
dc.subject.meshXeroderma Pigmentosum Group A Protein-
dc.titleInvolvement of MRE11A and XPA gene polymorphisms in the modulation of DNA double-strand break repair activity: a genotype-phenotype correlation study.en
dc.typeArticleen
dc.identifier.journalDNA Repairen

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