Ku86 represses lethal telomere deletion events in human somatic cells

Abstract

NHEJ ͉ rAAV ͉ t-circles ͉ DNA-PK ͉ homologous recombination T he repair of DNA double-strand breaks (DSBs) is important for cellular survival, the maintenance of genomic integrity, and the prevention of tumorigenesis. DSBs can be caused by exposure to exogenous agents, including ionizing radiation and chemotherapeutic agents, and be generated by endogenous mechanisms, such as variable(diversity)joining [V(D)J] and class-switch recombination-processes required for the maturation of B and T lymphocytes. Moreover, the ends of linear chromosomes present cells with naturally occurring DSBs-i.e

Ku's essential role in keeping telomeres intact

“…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.…”

“…Last, the finding of human Ku's essential telomeric function by Wang et al (5) underscores the point that as much as there are common themes in how organisms maintain telomere structure and function there can also be significant differences even between two closely related organisms such as humans and mice. Prior analyses of Ku have indicated that its involvement at the telomere varies greatly among species (3).…”

“…Regardless of the mechanism, what makes the work by Wang et al (5) particularly important is that it will bring Ku more center stage in the study of human telomeres. For many years studies on mammalian telomere end protection have focused on the shelterin complex, which is a key player at mouse and human telomeres (8).…”

Shelterin complex and associated factors at human telomeres

“…The Ku80 gene being essential, a conditional Cre-mediated Ku80 knock-out was created in order to study the complete loss of function. 137 Removal of the gene led to immediate cell death, accompanied with significant levels of double stranded breaks and, strikingly, a high degree of telomere loss. This loss was the consequence of the production of t-circles, which are believed to be the products of uninhibited recombination, producing t-loop-sized telomeric circular DNA molecules.…”

Reprint of “The clinical impact of deficiency in DNA non-homologous end-joining”

“…which is not reflected in animal models; Ku is essential for viability in human but not rodent cells and loss of DNA-PKcs, although not essential, has a marked impact on proliferative capacity [77,78]. The available evidence suggested that the essential function may lie in telomere maintenance.…”