title: Breaks at telomeres and TRF2-independent end fusions in Fanconi anemia.
abstract: Fanconi anemia (FA) is a rare genetic disease characterized by chromosome instability, progressive pancytopenia and cancer susceptibility. Telomeres are intimately related to chromosome stability and play an important role in organismal viability at the hematological level. Since previous works suggested an accelerated shortening of telomeres in FA, we have studied several markers of telomere integrity and function in FA patients and age-matched controls to get insights into the mechanisms and consequences of telomere erosion in FA. A higher frequency of extra-chromosomic TTAGGG signals and of chromosome ends with undetectable TTAGGG repeats was observed in FA cells by fluorescence in situ hybridization (FISH), suggesting intensive breakage at telomeric sequences. This was proven by measuring the frequency of excess of telomeric signals per cell, which was 2.8-fold higher in FA. Consistent with previous reports, quantitative FISH analysis showed an accelerated telomere shortening of 0.68 kb in FA, which occurred concurrently in both chromosome arms in a similar magnitude. Our data therefore suggest that the telomere erosion in FA is caused by a higher rate of breakage at TTAGGG sequences in vivo in differentiated cells, in addition to mere replicative shortening during lymphocyte proliferation. Consistent with impaired telomeres in FA patients, we observed a >10-fold increase in chromosome end fusions in FA compared to normal controls. This observation was independent of TRF2, a telomere binding factor that protects human telomeres from end fusions, since immunohistochemistry studies in FA cell lines and corrected counterparts by retrovirus-mediated transfer of FANCA and FANCD2 cDNA showed that a functional FA pathway is not required for telomere binding of TRF2.
authors.affiliation: Group of Mutagenesis, Department of Genetics and Microbiology, Universitat Autònoma de Barcelona, 08193 Bellaterra, Barcelona, Spain.
authors.forename: Elsa
authors.initials: E
authors.lastname: Callén
authors.forename: Enrique
authors.initials: E
authors.lastname: Samper
authors.forename: María J
authors.initials: MJ
authors.lastname: Ramírez
authors.forename: Amadeu
authors.initials: A
authors.lastname: Creus
authors.forename: Ricard
authors.initials: R
authors.lastname: Marcos
authors.forename: Juan J
authors.initials: JJ
authors.lastname: Ortega
authors.forename: Teresa
authors.initials: T
authors.lastname: Olivé
authors.forename: Isabel
authors.initials: I
authors.lastname: Badell
authors.forename: María A
authors.initials: MA
authors.lastname: Blasco
authors.forename: Jordi
authors.initials: J
authors.lastname: Surrallés
mesh_terms: D000293:Adolescent; D000328:Adult; D002648:Child; D002675:Child, Preschool; D002869:Chromosome Aberrations; D004268:DNA-Binding Proteins / Q000378:metabolism; D005199:Fanconi Anemia / Q000235:genetics*; D005260:Female; D006801:Humans; D008297:Male; D011485:Protein Binding; D016615:Telomere / Q000473:pathology; D035341:Telomeric Repeat Binding Protein 2
chemical_list: D004268:DNA-Binding Proteins; D035341:Telomeric Repeat Binding Protein 2