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Roles of the RNAi pathway in making telomere-free chromosome ends

Begnis, M; (2016) Roles of the RNAi pathway in making telomere-free chromosome ends. Doctoral thesis , UCL (University College London).

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Abstract

The discovery of a new mode of telomerase minus survival, ‘HAATI’, shook the dogma that canonical telomeres are essential to maintain linear chromosomes (Jain et al., 2010). In HAATI cells, telomeric sequences are superseded by blocks of generic heterochromatin, which jump to all chromosome ends and acquire the ability to protect them from fusions and degradation. While they lack of detectable telomeric repeats, these newly acquired termini recruit the canonical end-protection factor Pot1 and guarantee end protection. The amplified elements in HAATI are repetitive sequences associated with heterochromatin. Most commonly, the ribosomal DNA (rDNA) is the preferred substrate for this spreading to all chromosome ends. However, in a rare subset of cases, the SubTelomeric Elements (STE) can carry out this unconventional end-protective function; however, unlike HAATIrDNA, HAATISTE involves the amplification of STE repeats to internal as well as terminal genomic sites and thus is associated with a drastic genomic disruption. Here we show that the RNA interference pathway (RNAi) is absolutely required for HAATIrDNA formation. RNAi is specifically necessary for the jumping of rDNA between different chromosome ends. Moreover, we find that sequence jumping is the sole limiting event in HAATI formation. Intriguingly, we have also identified a new role for Dicer (Dcr1), the RNase component of the canonical RNAi pathway. Dicer actively inhibits the formation of HAATISTE-like survivors by repressing the amplification of the telomere-proximal STE repeats. Surprisingly, Dicer acts independently of the rest of the RNAi pathway in carrying out this genome-surveillance function. Our results disclose the importance of heterochromatin and ncRNAs in dictating the fates of unprotected chromosome ends and suggest avenues for uncovering mechanisms cancer cells might exploit in escaping the requirement for telomerase activation.

Type: Thesis (Doctoral)
Title: Roles of the RNAi pathway in making telomere-free chromosome ends
Event: UCL (University College London)
Language: English
UCL classification: UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences
URI: http://discovery.ucl.ac.uk/id/eprint/1474057
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