During mitosis, cohesins hold the sister chromatids together until anaphase when arm cohesins are removed （Peters et al., 2008; Yao and Dai, 2012）. The shugoshin （Sgo） proteins play pivotal roles during this stage. There is only one shu- goshin in the fly and budding yeasts, while there are two in other organisms （including fission yeasts）. The two mamma- lian shugoshins, Sgol and Sgo2, carry out distinct functions： Sgol mainly in mitosis, and Sgo2 mainly in meiosis and perturbed mitosis. Mitotic cyclin-dependent kinase 1 （CDKI） phosphorylates Sgol, and targets the Sgol-protein phospha- tase 2A （PP2A） complex to protect centromeric cohesin （Kitajima et al., 2006; Tang et al., 2006; Liu et al., 2012）,
DNA damage response (DDR) is among the most important of the mechanisms that maintain genome stability which, when destabilized, predisposes organs to cancer. Reversible phosphorylation mediated by protein kinases and protein phosphatases regulates most, if not all, cellular activities, including DDR. Protein kinase inhibitors have become the main focus of targeted therapy and anticancer drug development. However, our limited knowledge of protein phosphatase function is compromising our capacity to develop therapeutic agents against phosphatases. In this review, we summarize the roles of serine/threonine protein phosphatases involved in DDR and propose that in situ dephosphorylation of phosphoproteins by protein phosphatases, instead of proteasome-mediated degradation of phosphoproteins, is mainly employed by cells.
DNA double-strand break(DSB) is the most severe form of DNA damage,which is repaired mainly through high-fidelity homologous recombination(HR) or error-prone non-homologous end joining(NHEJ).Defects in the DNA damage response lead to genomic instability and ultimately predispose organs to cancer.Nicotinamide phosphoribosyltransferase(Nampt),which is involved in nicotinamide adenine dinucleotide metabolism,is overexpressed in a variety of tumors.In this report,we found that Nampt physically associated with CtIP and DNA-PKcs/Ku80,which are key factors in HR and NHEJ,respectively.Depletion of Nampt by small interfering RNA(siRNA) led to defective NHEJ-mediated DSB repair and enhanced HR-mediated repair.Furthermore,the inhibition of Nampt expression promoted proliferation of cancer cells and normal human fibroblasts and decreased β-galactosidase staining,indicating a delay in the onset of cellular senescence in normal human fibroblasts.Taken together,our results suggest that Nampt is a suppressor of HR-mediated DSB repair and an enhancer of NHEJ-mediated DSB repair,contributing to the acceleration of cellular senescence.
