NUAK1 links genomic instability and senescence

The AMP-activated protein kinase-related kinase (ARK) family comprises 13 proteins, amongst them NUAK1, that can be classified into five subfamilies: AMP-activated protein kinase (AMPK), salt-induced kinase (SIK), microtubule-affinity-regulating kinase (MARK), brain specific kinase (BRSK), and SNF1-like kinase 1 (NUAK). These proteins regulate biological responses such as metabolism, polarity, cell proliferation or cell death, presumably in a sub-family specific manner [1]. Although the different proteins regulate different responses, their activities are thought to be controlled by the same kinase, LKB1 [2], which phosphorylates a threonine residue in the conserved T-loop of ARK proteins. AMPK proteins are phosphorylated and activated by LKB1 when ATP levels decrease, whereas ARK proteins are phosphory-lated and activated independently of intracellular ATP levels [1]. During metabolic stress, ATP levels decrease and LKB1 activates AMPK that, in turn, phosphorylates a subset of proteins. P53 has been identified as one of these proteins, and it is postulated that the phosphorylation and activation of p53 by AMPK leads to cell cycle arrest and senescence [3]. We have recently identified and described the role of NUAK1 in the regulation of replicative senescence. Indeed, the constitutive expression of NUAK1 induces senescence in WI38 normal human fibroblasts whereas its knockdown extends their replicative lifespan. The loss of NUAK1 activation by LKB1 (by using a NUAK1 Editorial NUAK1 mutant unresponsive to LKB1 or by inhibiting LKB1 activity in NUAK1 expressing cells) results in a failure of NUAK1 to induce senescence, thus demonstrating the major role of LKB1 in NUAK1-induced senescence. Interestingly, our results support the existence of a p53 independent response, at least in WI38 cells, and emphasize a potential role of aneuploidy in NUAK1-dependent senescence [4]. Aneuploidy and senescence Aneuploidy or genomic instability due to various factors have been reported to induce senescence [5,6,7]. Interestingly, senescent cells often display elevated aneuploidy, which suggests a putative functional role of aneuploidy in senescence. Nevertheless, it is unclear whether aneuploidy is involved in the establishment of the senescent phenotype and, if prevented, it can impair senescence, at least to some extent. A breakthrough has been achieved with the demonstration that the state of irreversible growth arrest in senescent cells may be due to elevated aneuploidy, putatively through a decrease of LATS1, a kinase involved in mitotic exit [7]. These results suggest that aneuploidy, if not directly involved in the establishment of senescence, can be required for irreversible growth arrest in senescent cells. Interestingly, aneuploidy was also …