Telomeres are essential for maintaining the integrity of the genome. Shortening and dysfunction of telomeres initiates cellular senescence, halting further cell division, and instigating alterations in biological processes which contribute to ageing. Progeroid syndromes are disorders of ageing. Patients exhibit not only an early external appearance of old age, but several age-related diseases including osteoporosis, muscle wasting and cancer. Laminopathies are diseases caused by mutations in LMNA, the gene encoding the key nuclear matrix component lamin A. Some mutations result in progeroid phenotypes that are associated with elevated levels of senescent cells. The rate of telomere shortening in progeria cells was found to be accelerated relative to healthy controls, confirming a role for lamin A function in telomere biology. In order for a cell to bypass the protective mechanism of senescence, it must initiate a telomere maintenance mechanism (TMM), resulting in cancer. Several biological changes accompanying the alternative lengthening of telomeres (ALT) TMM overlap with mechanisms affected by changes in lamin biology. As such, lamins and related nuclear proteins were investigated in ALT cells and found to differ from tumour-derived cells which activate the telomerase-based TMM. It was found that although nuclear levels of lamins differed between cells of the two TMMs, the interaction of lamin A with chromatin was not altered. Localisation studies of lamin A revealed different distribution of lamins in the nucleus. An excess of intranuclear lamin observed in ALT cells is proposed to be permissive for recombination-based processes required for telomere elongation through ALT, whereas laminopathy lines exhibit a reduced intranuclear lamin, and an accompanying DNA damage repair deficiency. These findings reinforce the importance of lamin organisation and intranuclear network stability in chromatin maintenance, and highlight a new role for lamins in ALT cancers.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:647119 |
| Date | January 2015 |
| Creators | Turner, Rachel |
| Contributors | Royle, Nicola; Shackleton, Sue |
| Publisher | University of Leicester |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Source | http://hdl.handle.net/2381/32257 |
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