Ku's essential role in keeping telomeres intact

Abstract

Telomeres, the specialized nucleoprotein structures present at the ends of linear chromosomes, function to prevent natural chromosomal termini from activating the DNA damage response and becoming substrates for inappropriate DNA repair. Telomeres are organized into lariat-like structures known as t-loops, which are formed by the invasion of the terminal G-rich 3′ telomeric overhang into the proximal duplex telomeric tract on the same chromosome (1) (Fig. 1). T-loops have been proposed to be a crucial means by which the telomeric end is hidden from DNA double strand break (DSB) repair pathways, with nonhomologous end joining (NHEJ) being the dominant mechanism of DSB repair in mammalian cells. Consequently, when telomeres become dysfunctional, and presumably no longer able to form t-loops, they can be engaged in NHEJ, giving rise to chromosome end-to-end fusions (2). Paradoxically, the Ku70/Ku86 heterodimer, a central component of NHEJ, is important at functional telomeres. There, instead of mediating NHEJ, Ku has been shown to contribute to various aspects of telomere structure and function. For example, Ku has been found to protect telomeres from inappropriate degradation and interchromosomal recombination and contribute to the tethering of telomeres to the nuclear periphery and the regulation of telomerase (3). Although Ku has a conserved role in NHEJ and appears to have at least one or more roles at the telomere across species, only in humans has it been shown to be an essential protein (4). The reason has been unknown, but it has been speculated that Ku's essential function lies in its telomeric, not NHEJ, role. In this issue of PNAS, Wang et al. (5) have not only confirmed this speculation but have revealed that Ku's essential role in human cells is to prevent dramatic telomere loss.