Telomeres are the ends of linear chromosomes which are protected by a multi-protein complex called shelterin. The proper maintenance of telomeres involves strict control over the length of the TTAGGG telomeric repeat sequences. In part, this is achieved through the action of the shelterin complex component TRF1. TRF1 binds to duplex telomere DNA and acts as a suppressor of telomerase-dependent telomere elongation, however the exact mechanism by which it achieves this is currently unknown. Recent observations with a phospho-specific TRF1 antibody indicate that phosphorylated (pT371)TRF1 localizes at Cajal bodies. Cajal bodies are subnuclear organelles with myriad functions, one of which is to recruit the subunits of the telomerase holoenzyme for assembly and the subsequent targeting of the enzyme to telomeres for elongation. The results presented here demonstrate that this association of phosphorylated (pT371)TRF1 to Cajal bodies is highly specific, requiring its DNA binding capability, and occurring only in Cajal bodies which are not actively involved with telomere extension. While the function of this association has not been elucidated, the data are suggestive of a telomerase-related role being played by phosphorylated (pT371)TRF1 at Cajal bodies, possibly related to its function in suppressing telomere elongation.
CSB is a multifunction protein which is implicated in transcription-coupled repair (TCR), base excision repair (BER), and control of transcription. Certain mutations and truncations of CSB are known to cause Cockayne syndrome (CS) in humans, an autosomal recessive progeria with devastating consequences. Unlike other progeria, CS patients do not display increased cancer incidence. Despite this fact, CSB is upregulated and in many cancers. In these cells, removal of CSB leads to apoptosis and increased sensitivity to chemotherapeutic drugs which suggests a dependency on CSB. The CSB of some non-CS cancer patients has also been found to be mutated at several recurring SNPs through the CSB gene. Preliminary examination of some of these SNPs suggests that they may invoke a change in the efficiency of TCR repair of UV-induced DNA damage. The results presented here demonstrate that, for the SNPs examined, there is no significant change in the repair of UV damage as assessed by colony survival assays post UV-treatment. While this may rule out an effect on TCR by these cancer-associated SNPs, it is possible that they may have an effect on CSB’s involvement in other vital cellular processes. / Thesis / Master of Science (MSc)
| Identifer | oai:union.ndltd.org:mcmaster.ca/oai:macsphere.mcmaster.ca:11375/16297 |
| Date | 11 1900 |
| Creators | Gurecki, Michael J |
| Contributors | Zhu, Xu-Dong, Biology |
| Source Sets | McMaster University |
| Language | en_US |
| Detected Language | English |
| Type | Thesis |
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