title: The R280H X-ray cross-complementing 1 germline variant induces genomic instability and cellular transformation.
abstract: X-ray repair cross complementing protein 1 (XRCC1) plays an important role in base excision DNA repair (BER) as a scaffolding protein for BER enzymes. BER is one of the basic DNA repair pathways repairing greater than 20,000 endogenous lesions per cell per day. Proper functioning of XRCC1, one of the most important players in BER, was suggested to be indispensable for effective DNA repair. Despite accumulating evidence of an important role that XRCC1 plays in maintaining genomic stability, the relationship between one of its most predominant variants, R280H (rs25489), and cancer prevalence remains ambiguous. In the current study we functionally characterized the effect of the R280H variant expression on immortal non-transformed mouse mammary epithelial C127 and human breast epithelial MCF10A cells. We found that expression of R280H results in increased focus formation in mouse C127 cells and induces cellular transformation in human MCF10A cells. Cells expressing R280H showed significantly increased levels of chromosomal aberrations and accumulate double strand breaks in the G1 cell cycle phase. Our results confirm a possible link between R280H and genomic instability and suggest that individuals carrying this mutation may be at increased risk of cancer development.
authors.affiliation: Department of Therapeutic Radiology, Yale University School of Medicine, 333 Cedar Street, New Haven, CT 06437, USA.
authors.forename: Daria V
authors.initials: DV
authors.lastname: Sizova
authors.affiliation: Department of Therapeutic Radiology, Yale University School of Medicine, 333 Cedar Street, New Haven, CT 06437, USA.
authors.forename: Agnes
authors.initials: A
authors.lastname: Keh
authors.affiliation: Department of Therapeutic Radiology, Yale University School of Medicine, 333 Cedar Street, New Haven, CT 06437, USA.
authors.forename: Ben F
authors.initials: BF
authors.lastname: Taylor
authors.affiliation: Department of Therapeutic Radiology, Yale University School of Medicine, 333 Cedar Street, New Haven, CT 06437, USA. Electronic address: joann.sweasy@yale.edu.
authors.forename: Joann B
authors.initials: JB
authors.lastname: Sweasy
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000235:genetics; D002453:Cell Cycle; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D003001:Cloning, Molecular; D053903:DNA Breaks, Double-Stranded; D004260:DNA Repair; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D005260:Female; D016193:G1 Phase; D015972:Gene Expression Regulation, Neoplastic; D014644:Genetic Variation; D042822:Genomic Instability; D006801:Humans; D051379:Mice; D012307:Risk Factors; D000076105:X-ray Repair Cross Complementing Protein 1
chemical_list: D004268:DNA-Binding Proteins; D000076105:X-ray Repair Cross Complementing Protein 1; C000619371:XRCC1 protein, human; C000619352:Xrcc1 protein, mouse
keywords: Alternative end joining; Base excision repair; X-ray cross complementing 1