Ku circles the telomere?

all tumor cells are created equal when it comes to telomere biology. Tumor cells that do not express telomerase appear to utilize a telomerase-independent process to maintain telomere length, known as ALT for alternative lengthening of telomeres [1]. Although the existence of this process has been recognized for some time, the precise mechanism by which telomeres are maintained in these cells has been difficult to determine [2]. A recent report introduces a new element into the ALT story, implicating the Ku70/80 protein heterodimer (simply referred to as Ku) in the ALT process. Work reported by Li and coworkers in this issue of Aging, reveals a novel requirement for Ku in maintaining telomeres in immortal cells that utilize ALT [3]. The authors present data using a gene targeting approach to deplete both Ku subunits in two independent ALT cell lines. The ALT cells succumb to a combination of senescence and apoptosis without loss of telomere length or single-stranded telomere overhang. Surprisingly, the production of extra chromosomal DNA circles (t-circles) is reduced following Ku depletion as it is following depletion of MRE11/NBS1, known requirements for t-circle formation [4]. The results are striking because the Ku heterodimer is a central element in the nonhomologous end joining (NHEJ) DNA repair pathway, as it binds preferentially to free DNA ends and functions to recruit components of NHEJ DNA repair such as DNA-dependent protein kinase (DNAPK) and ligase IV. Although the Ku heterodimer is intimately involved in DNA repair, it has become apparent that Ku also participates in a wide variety of functions related to genome integrity. For example, Ku has been localized to origins of replication, and has been implicated in chromatin remodeling required for transcriptional activation and in telomere maintenance [5]. Ku also Commentary appears to play a role in aging. Deletion of the Ku 80 gene leads to an immune-deficient phenotype due to loss of proper VDJ recombination, but also induces a premature aging phenotype [6]. Ku 80 levels and DNA end binding also show a striking exponential correlation with species lifespan [7], suggesting that increased Ku function is requisite for long-lived species. Additionally, Ku levels decrease during replicative senescence [8]. Consistent with a higher requirement for Ku function in long-lived species, Ku appears to play an essential role in human cells while it is dispensable in rodent cells [9]. Ku has also been identified as a nodal point in systems analysis of …