title: Lower level of BRCA2 protein in heterozygous mutation carriers is correlated with an increase in DNA double strand breaks and an impaired DSB repair.
abstract: The BRCA2 protein is involved in the maintenance of genomic stability through its key role in homologous recombination repair of DNA double strand breaks. Biallelic inactivation of BRCA2 leads to a defect in DNA repair and is associated with a chromosomal instability phenotype. Recent studies on familial breast cancer clusters revealed chromosomal rearrangements and higher rates of sister chromatid exchanges also in heterozygous BRCA2 mutation carriers. In the present study, lymphoblastoid cell lines of heterozygous BRCA2 mutation carriers and of wildtype relatives were compared with regard to BRCA2 mRNA and protein expression and capacity to repair DNA damage induced by gamma-irradiation and mitomycin C. BRCA2+/- cells showed lower amounts of the full-length BRCA2 protein compared to BRCA2+/+ cells. The kinetics of gamma-H2AX protein level revealed distinct defects in DNA double strand break repair in the BRCA2+/- cells. These results are indicative of a haploinsufficiency phenotype in BRCA2+/- cells, suggesting that reduced amounts of functional BRCA2 protein in BRCA2+/- carriers are insufficient for an efficient repair of DNA double strand breaks, a condition that could contribute to the impairment of genomic stability.
authors.affiliation: Department of Tumour Genetics B030, German Cancer Research Center, Im Neuenheimer Feld 280, 69120 Heidelberg, Germany. k.arnold@dkfz.de <k.arnold@dkfz.de>
authors.forename: Katrin
authors.initials: K
authors.lastname: Arnold
authors.forename: Min-Kyoung
authors.initials: MK
authors.lastname: Kim
authors.forename: Katrin
authors.initials: K
authors.lastname: Frerk
authors.forename: Lutz
authors.initials: L
authors.lastname: Edler
authors.forename: Larissa
authors.initials: L
authors.lastname: Savelyeva
authors.forename: Peter
authors.initials: P
authors.lastname: Schmezer
authors.forename: Ruprecht
authors.initials: R
authors.lastname: Wiedemeyer
mesh_terms: D000704:Analysis of Variance; D024682:BRCA2 Protein / Q000235:genetics / Q000378:metabolism*; D001483:Base Sequence; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D018567:Breast Neoplasms, Male / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D002453:Cell Cycle / Q000235:genetics / Q000502:physiology; D002460:Cell Line; D020552:Comet Assay; D004247:DNA / Q000737:chemistry / Q000235:genetics; D004249:DNA Damage / Q000235:genetics*; D004252:DNA Mutational Analysis; D004260:DNA Repair / Q000235:genetics*; D005260:Female; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D005720:Gamma Rays; D006239:Haplotypes / Q000235:genetics; D006579:Heterozygote; D006801:Humans; D008297:Male; D016685:Mitomycin / Q000494:pharmacology; D009154:Mutation / Q000187:drug effects / Q000235:genetics* / Q000528:radiation effects; D010375:Pedigree; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D024682:BRCA2 Protein; D012333:RNA, Messenger; D016685:Mitomycin; D004247:DNA