Which end: dissecting Ku's function at telomeres and double-strand breaks

The ends of chromosomes are active places. These natural DNA termini must be protected from degradation, recombination, and end-to-end fusions—events that would be ultimately fatal for the genome. In addition, the enzyme telomerase ensures that telomeres in proliferating cells, such as single-celled organisms like budding yeast or the mammalian germ line, are completely replicated. Over the past decade, a plethora of telomere-associated proteins have been identified, based on their ability to regulate telomerase access, provide protection from nucleases and recombinases, and control telomere length (for review, see McEachern et al. 2000; de Lange 2002). In the budding yeast, at least a dozen proteins interact with just the terminal single-stranded overhang, with an additional dozen or more proteins that are associated with the duplex region of the telomere. At mammalian telomeres, which are bound by additional factors that are apparently not present in yeast, the situation is even more complex.

To make the task of understanding events that take place at telomeres even more challenging, many telomere-associated proteins perform more than one biochemical activity at chromosome ends. For example, in human cells, the telomere repeat binding factor TRF2 protects chromosomes from end-to-end fusions, and also acts as a negative regulator of telomere length (van Steensel et al. 1998; Loayza and De Lange 2003). The yeast telomere end-binding factor Cdc13 similarly performs several discrete tasks: Cdc13 both positively and negatively regulates telomere elongation by telomerase, as well as shields chromosome termini from unregulated degradation by nucleases (Garvik et al. 1995; Nugent et al. 1996; Booth et al. 2001; Chandra et al. 2001). Analyses of these Cdc13-mediated processes have been greatly aided by separation-of-function mutations that appear to selectively impair each activity. In an analogous manner, recent genetic studies of the catalytic subunit of telomerase have helped to …