title: Genomic rearrangements at the FRA2H common fragile site frequently involve non-homologous recombination events across LTR and L1(LINE) repeats.
abstract: Common fragile sites (cFSs) are non-random chromosomal regions that are prone to breakage under conditions of replication stress. DNA damage and chromosomal alterations at cFSs appear to be critical events in the development of various human diseases, especially carcinogenesis. Despite the growing interest in understanding the nature of cFS instability, only a few cFSs have been molecularly characterised. In this study, we fine-mapped the location of FRA2H using six-colour fluorescence in situ hybridisation and showed that it is one of the most active cFSs in the human genome. FRA2H encompasses approximately 530 kb of a gene-poor region containing a novel large intergenic non-coding RNA gene (AC097500.2). Using custom-designed array comparative genomic hybridisation, we detected gross and submicroscopic chromosomal rearrangements involving FRA2H in a panel of 54 neuroblastoma, colon and breast cancer cell lines. The genomic alterations frequently involved different classes of long terminal repeats and long interspersed nuclear elements. An analysis of breakpoint junction sequence motifs predominantly revealed signatures of microhomology-mediated non-homologous recombination events. Our data provide insight into the molecular structure of cFSs and sequence motifs affected by their activation in cancer. Identifying cFS sequences will accelerate the search for DNA biomarkers and targets for individualised therapies.
authors.affiliation: Division of Tumor Genetics, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120 Heidelberg, Germany.
authors.forename: Lena M
authors.initials: LM
authors.lastname: Brueckner
authors.forename: Evgeny
authors.initials: E
authors.lastname: Sagulenko
authors.forename: Elisa M
authors.initials: EM
authors.lastname: Hess
authors.forename: Diana
authors.initials: D
authors.lastname: Zheglo
authors.forename: Anne
authors.initials: A
authors.lastname: Blumrich
authors.forename: Manfred
authors.initials: M
authors.lastname: Schwab
authors.forename: Larissa
authors.initials: L
authors.lastname: Savelyeva
mesh_terms: D001483:Base Sequence; D045744:Cell Line, Tumor; D043283:Chromosome Fragile Sites; D022202:Chromosomes, Artificial, Bacterial; D002889:Chromosomes, Human, Pair 2; D055028:Comparative Genomic Hybridization; D017931:DNA Primers; D015321:Gene Rearrangement; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D020084:Long Interspersed Nucleotide Elements; D016133:Polymerase Chain Reaction; D011995:Recombination, Genetic
chemical_list: D017931:DNA Primers