Ku circles the telomere?

摘要: Not all tumor cells are created equal when it comes to telomere biology. Tumor that do not express telomerase appear utilize a telomerase-independent process maintain length, known as ALT for alternative lengthening of telomeres [1]. Although the existence this has been recognized some time, precise mechanism by which maintained in these difficult determine [2]. A recent report introduces new element into story, implicating Ku70/80 protein heterodimer (simply referred Ku) process. Work reported Li and coworkers issue Aging, reveals novel requirement Ku maintaining immortal [3]. The authors present data using gene targeting approach deplete both subunits two independent cell lines. succumb combination senescence apoptosis without loss length or single-stranded overhang. Surprisingly, production extra chromosomal DNA circles (t-circles) is reduced following depletion MRE11/NBS1, requirements t-circle formation [4]. results striking because central nonhomologous end joining (NHEJ) repair pathway, binds preferentially free ends functions recruit components NHEJ such DNA-dependent kinase (DNAPK) ligase IV. intimately involved repair, become apparent also participates wide variety related genome integrity. For example, localized origins replication, implicated chromatin remodeling required transcriptional activation maintenance [5]. appears play role aging. Deletion 80 leads an immune-deficient phenotype due proper VDJ recombination, but induces premature aging [6]. levels binding show exponential correlation with species lifespan [7], suggesting increased function requisite long-lived species. Additionally, decrease during replicative [8]. Consistent higher species, essential human while dispensable rodent [9]. identified nodal point systems analysis aging-related genes [10]. multiple seems depend upon specific biology [11]. Nonetheless, be complex forms at telomere. normal positive [9, 12]. Interestingly, differs each settings. In fibroblasts, reduction rapid combined decreased key protein, TRF2, chromatin. cells, induced. Most surprising contrasting effect on t-circles diagnostic [13]. Depletion work et al. demonstrates t-circles. fibroblasts critical cycle progression rapidly senesce depletion. This likely precludes development either fusions seen cells. different scenario occurs incorporated responsible production, leading their What common denominator between types linking function? One possibility association core telomere-associated proteins TRF2. 70 found directly interact TRF2 [14]. hub complexes [15] interaction may important prevent [16]. [12], stabilize TRF2-mediated complexes. Given altering influences [17], necessary formation. addition, structural characteristics telomerase-positive differ, providing another potential explanation differential roles greater understanding mechanisms will require additional experimentation, however, provides evidence serves very can vary varies, even suggests least subset lines, resolution telomere-induced genomic crisis have undergone clonal evolution.