Molecular Mechanisms and Control of Alternative Lengthening of Telomeres

癌细胞用来保护其染色体末端的机制的研究细胞核内的DNA被排列在称为染色体的线性包装中，在每个末端被称为端粒的结构所覆盖。端粒由一长段不含任何基因的重复DNA序列组成。大多数正常细胞无法复制染色体末端的DNA，因此每次分裂时，端粒都会变短。这最终阻止了细胞进一步分裂，并成为细胞癌变的一个非常有效的屏障。有些正常细胞不受这种不可阻挡的端粒缩短的影响：这些是睾丸和卵巢中的生殖细胞，负责将遗传物质传递给下一代。这些细胞表达一种酶，端粒酶，它能够合成新的端粒DNA来取代细胞分裂过程中丢失的DNA。85%的人类癌症也能够通过端粒酶活性阻止端粒缩短，从而突破了通常阻止细胞无限增殖的屏障。因此，如果能够开发出抑制端粒酶的药物，它们可能是一种非常有用的癌症治疗新形式。然而，我们已经发现，一些癌症能够通过不涉及端粒酶的过程来防止端粒缩短，我们称之为端粒替代性延长（ALT）。这一发现对设计新的癌症治疗方法的一个实际意义是，端粒酶抑制剂需要与ALT抑制剂联合使用。在本研究中，我们将确定A。正常细胞如何保持ALT机制永久关闭和B. ALT机制本身的分子细节对这些过程的理解可能最终有助于开发新的癌症治疗方法，破坏癌细胞无限次分裂的能力。

Studies of a mechanism cancer cells use to protect the ends of their chromosomes The DNA within cell nuclei is arranged in linear packages referred to as chromosomes, capped at each end by structures called telomeres. Telomeres consist of a long stretch of a repetitive DNA sequence that does not contain any genes. Most normal cells are unable to copy the DNA at the extreme ends of their chromosomes, so every time they divide their telomeres get slightly shorter. This ultimately stops the cell from dividing any further, and acts as a very potent barrier to the cell becoming cancerous. Some normal cells are not subject to this inexorable telomere shortening: these are the germ cells in the testis and ovary, that are responsible for passing on genetic material to the next generation. Such cells express an enzyme, telomerase, which is able to synthesise new telomeric DNA to replace that lost during cell division. 85% of human cancers are also able to prevent shortening of their telomeres - and thus have breached the barrier that normally prevents unlimited cell proliferation - via telomerase activity. Therefore, if drugs that inhibit telomerase can be developed they may be a very useful new form of cancer treatment. We have found, however, that some cancers are able to prevent telomere shortening by a process that does not involve telomerase, and which we refer to as Alternative Lengthening of Telomeres (ALT). One practical implication of this finding for the design of new cancer treatments is that telomerase inhibitors will need to be used in combination with ALT inhibitors. In this study, we will determine A. how normal cells keep the ALT mechanism permanently shut down and B. the molecular details of the ALT mechanism itself. An understanding of these processes may ultimately contribute to the development of novel cancer treatments that disrupt the ability of cancer cells to divide an unlimited number of times.