Molecular characterisation of a mosaicism with a complex chromosome rearrangement: evidence for coincident chromosome healing by telomere capture and neo-telomere formation

Abstract

Background: Broken chromosomes must acquire new telomeric ''caps'' to be structurally stable. Chromosome healing can be mediated either by telomerase through neo-telomere synthesis or by telomere capture. Aim: To unravel the mechanism(s) generating complex chromosomal mosaicisms and healing broken chromosomes. Methods: G banding, array comparative genomic hybridization (aCGH), fluorescence in-situ hybridisation (FISH) and short tandem repeat analysis (STR) was performed on a girl presenting with mental retardation, facial dysmorphism, urogenital malformations and limb anomalies carrying a complex chromosomal mosaicism. Results & discussion: The karyotype showed a de novo chromosome rearrangement with two cell lines: one cell line with a deletion 9pter and one cell line carrying an inverted duplication 9p and a non-reciprocal translocation 5pter fragment. aCGH, FISH and STR analysis enabled the deduction of the most likely sequence of events generating this complex mosaic. During embryogenesis, a double-strand break occurred on the paternal chromosome 9. Following mitotic separation of both broken sister chromatids, one acquired a telomere via neotelomere formation, while the other generated a dicentric chromosome which underwent breakage during anaphase, giving rise to the del inv dup(9) that was subsequently healed by chromosome 5 telomere capture. Conclusion: Broken chromosomes can coincidently be rescued by both telomere capture and neo-telomere synthesis.

Ionizing Radiation Up-regulates Telomerase Activity in Cancer Cell Lines by Post-translational Mechanism via Ras/Phosphatidylinositol 3-Kinase/Akt Pathway

“…The results of our study are in concert with this general approach. Up-regulation of TA may represent a physiologic protective mechanism against DNA damage, contributing to DNA repair by chromosomal healing (48) and enhanced survival. This hypothesis is supported by studies such as of Akiyama et al, showing that overexpression of telomerase protects from apoptosis triggered by doublestranded DNA damage (49).…”

Cancer‐associated neochromosomes: a novel mechanism of oncogenesis

“…(1) One potential mechanism of stabilisation is activation of telomerase-dependent chromosome end healing. (26) This mechanism requires the TTAGGG repeat sequences as a substrate for telomere elongation by the telomerase holoenzyme complex. (27) Because the newly linearised CaNC will not contain canonical telomere repeat sequences, telomerase-dependent chromosome end healing is unlikely to occur.…”

Oculocerebral Hypopigmentation Syndrome Maps to Chromosome 3q27.1q29

“…BAC array comparative genomic hybridisation (aCGH) at a mean resolution of 1 Mb was performed as previously described [11]. Since only the patient’s DNA was still available, fluorescence in situ hybridisation could not be performed and the aCGH data were confirmed by real-time quantitative PCR (qPCR) and completed by genotyping using (CA) n repeat polymorphic marker analysis mapping to 3q27.1 (D3S1571, D3S3609, D3S3578) and to 3q29 (D3S3669, D3S3562) which, in addition, enabled to determine the parental origin of the abnormality.…”