Telomere maintenance pathways and their role in genome stability.

大多数癌细胞都有无限复制的能力。这部分是通过激活端粒维持机制（TMM）来实现的，我们正试图了解其中一些途径的分子基础。端粒是覆盖在染色体上的重复DNA序列，从而防止对基因组的损害。大多数肿瘤激活端粒酶或端粒选择性延长（ALT）途径来维持端粒，但TMM在一部分肿瘤中是未知的。此外，ALT的分子机制尚不清楚。最近，我们已经证明ALT通路的激活可以破坏基因组中其他重复序列的稳定性，但这一观察的意义尚不清楚。因此，利用单端粒和单分子方法，我们计划研究端粒DNA和其他序列，以阐明肿瘤中潜在的TMM。此外，在细胞系中，我们计划破坏被认为在ALT中起作用的基因的表达，并研究其对基因组中端粒和其他DNA序列的影响。从长远来看，我们希望这将导致确定新的抗癌疗法的目标。

Most cancer cells have the capacity to replicate indefinitely. This is partly achieved by activation of a telomere maintenance mechanism (TMM) and we are trying to understand the molecular basis of some of these pathways. Telomeres are repetitive DNA sequences that cap chromosomes and so prevent damage to the genome. The majority of tumours activate telomerase or the Alternative Lengthening of Telomeres (ALT) pathway to maintain telomeres but the TMM is unknown in a subset of tumours. In addition the molecular mechanism that underlies ALT is poorly understood. Recently we have shown that activation of the ALT pathway can destabilize other repeated sequences in the genome but the significance of this observation is unclear. Therefore using single telomere and single molecule approaches we plan to investigate telomeric DNA and other sequences in order to elucidate the underlying TMM in tumours. In addition in cell lines we plan to disrupt the expression of genes that are thought to play a role in ALT and study the effect on telomeres and other DNA sequences in the genome. In the long term we hope this will lead to identification of targets for novel anti-cancer therapies.