Abstract
BackgroundFanconi anemia (FA) is a chromosomal instability syndrome characterized by increased frequency of chromosomal breakages, chromosomal radial figures and accelerated telomere shortening. In this work we performed detailed molecular-cytogenetic characterization of breakpoints in primary lymphocytes of FA-D2 patients in different stages of the disease using fluorescent in situ hybridization.ResultsWe found that chromosomal breakpoints co-localize on the molecular level with common fragile sites, whereas their distribution pattern depends on the severity of the disease. Telomere quantitative fluorescent in situ hybridization revealed that telomere fusions and radial figures, especially radials which involve telomere sequences are the consequence of critically shortened telomeres that increase with the disease progression and could be considered as a predictive parameter during the course of the disease. Sex chromosomes in FA cells are also involved in radial formation indicating that specific X chromosome regions share homology with autosomes and also could serve as repair templates in resolving DNA damage.ConclusionsFA-D2 chromosomal breakpoints co-localize with common fragile sites, but their distribution pattern depends on the disease stage. Telomere fusions and radials figures which involve telomere sequences are the consequence of shortened telomeres, increase with disease progression and could be of predictive value.
Highlights
Fanconi anemia (FA) is a chromosomal instability syndrome characterized by increased frequency of chromosomal breakages, chromosomal radial figures and accelerated telomere shortening
Filipović et al Molecular Cytogenetics (2016) 9:70 breakages, Schoder and coworkers [8] reported that chromosomal breakpoints in cells derived from FA-A and FA-C patients co-localize with the chromosomal regions that are constitutionally prone to breakage in each individual, known as common fragile sites (CFSs)
The FA breakpoint analysis showed that frequency of breakages, and breakpoint distribution pattern depend on the stage of the disease: most of the breakpoints in both groups of patients corresponded to CFSs, except for patient 1 in groups accordingly: severe (group A) where one of the most frequent breaks was 1q42.2 (Fig. 1)
Summary
Fanconi anemia (FA) is a chromosomal instability syndrome characterized by increased frequency of chromosomal breakages, chromosomal radial figures and accelerated telomere shortening. 19 different complementation groups, which correspond to distinct DNA repair genes have been identified, FA-A, FA-B, FA-C, FA-D1 (BRCA2), FA-D2, FA-E, FA-F, FA-G, FA-I, FA-J (BRIP1), FA-M, FA-N (PALB2), FA-O (RAD51C), FA-P (SLX4), FA-Q (ERCC4), FA-S (BRCA1), FA-R (RAD51) and FA-T (UBE2T) [1]. The genes that correspond to different FA complementation groups are involved in the FA/BRCA DNA damage repair pathway having an essential function in the cellular response to stress. Filipović et al Molecular Cytogenetics (2016) 9:70 breakages, Schoder and coworkers [8] reported that chromosomal breakpoints in cells derived from FA-A and FA-C patients co-localize with the chromosomal regions that are constitutionally prone to breakage in each individual, known as common fragile sites (CFSs). The role of telomeres in formation of induced chromosomal aberrations such as radial figures has not been determined, yet
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