Telomere Damage Induces Internal Loops that Generate Telomeric Circles

Mazzucco, Giulia (2021). Telomere Damage Induces Internal Loops that Generate Telomeric Circles. PhD thesis The Open University.



Telomeres are essential in preventing the recognition of chromosome ends by the double-strand break (DSB) response, thereby permitting the maintenance of linear chromosomes. Extrachromosomal telomeric circles are important players in telomere maintenance, but little is known about their origin. We developed a new procedure for the purification of mammalian telomeric repeats in order to study telomere structures by Electron Microscopy (EM). Using this approach, we detected the expected telomeric features (i.e. t-loops) but we also found accumulation of internal loops (i-loops) at telomeric repeats that occur in the proximity of nicks and single-stranded DNA gaps. We showed that i-loops are induced by single-stranded damage at normal telomeres and represent the majority of the telomeric structures that accumulate in ALT (Alternative Lengthening of Telomeres) tumour cells, which are characterized by DNA damage accumulation at telomeric repeats. We also demonstrated that telomeric molecules containing i-loops can become a source of extrachromosomal telomeric circles. We propose that i-loops can form through strand exchange events at sites of damage, which are facilitated by the high sequence homology at telomeric repeats. This leads to the formation of intramolecular Holliday junctions that can be resolved to generate circular molecules made of telomeric DNA and resulting in a net loss of telomeric repeats. We propose that damage-induced i-loops are common intermediates in telomere maintenance that link telomere damage to the accumulation of extrachromosomal telomeric circles and to telomere erosion.

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