Detection of Alternative Lengthening of Telomeres in the Mouse

在每个细胞中，DNA被包装成称为染色体的单位，染色体的末端（即，端粒）在新细胞产生期间每次复制时都会变得稍微短一些。持续的细胞复制和端粒的不断缩短最终导致细胞无法进一步复制自己。正常细胞具有减缓端粒缩短的机制，但不能完全阻止端粒缩短。癌症的发展取决于其细胞能够多次复制自己，因此他们需要找到一种方法来防止端粒缩短。我们发现了一种被称为端粒替代延长（ALT）的方法，这种方法被一些癌症所使用。原则上已经表明，可以通过破坏癌细胞防止端粒缩短的能力来杀死癌细胞。因此，在另一个项目中，我们正在开发找到抑制ALT的药物所需的方法。与此同时，我们发现了一些正常细胞具有ALT样机制的第一个证据。我们的推测是，癌细胞能够失调并破坏这种正常机制，以防止其端粒缩短。在这个项目中，我们将分析小鼠中ALT样机制，以确定其特征，并确定哪些组织使用它。这些信息将为ALT机制本身以及抑制ALT的药物可能的副作用提供至关重要的见解。

In each cell, DNA is packaged into units called chromosomes, the ends of which (i.e., telomeres) become slightly shorter every time they are replicated during the production of new cells. Continued cell replication and hence continued telomere shortening eventually results in the inability of cells to replicate themselves any further. Normal cells have mechanisms to slow down, but not completely prevent telomere shortening. The development of a cancer depends on its cells being able to replicate themselves many times, and therefore they need to find a method to prevent their telomeres shortening. We discovered one such method, called Alternative Lengthening of Telomeres (ALT), that is used by some cancers. It has been shown in principle that cancer cells can be killed by disrupting their ability to prevent telomere shortening. Therefore, in another project we are developing methods needed to find drugs that inhibit ALT. In the meantime, we have found the first evidence that some normal cells have an ALT-like mechanism. Our speculation is that cancer cells are able to dysregulate and subvert this normal mechanism in order to prevent their telomeres from shortening. In this project, we will analyse the ALT-like mechanism in mice, to determine its characteristics, and to determine what tissues use it. This information will provide critically important insights into the ALT mechanism itself, and the likely side effects of drugs that inhibit ALT.