Cell Death Differ PMID: 24926618 (2014)
Zhang HH1, Li SZ1, Zhang ZY1, Hu XM1, Hou PN1, Gao L2, Du RL1, Zhang XD1.
The DNA damage response (DDR) acts as a protective mechanism for maintaining cell homeostasis. Nemo-like kinase (NLK) is a serine/threonine-protein kinase that has an important role in many pathways; however, its function in the DDR has not yet been defined. In our study, NLK-deficient HCT116 cells were found to be resistant to etoposide-induced cell death. We demonstrated that NLK is required for p53 activation in response to DNAdamage. Remarkably, mechanistic studies revealed that NLK interacts with p53 and stabilizes p53 by blocking MDM2-mediated p53 ubiquitination and degradation. Furthermore, NLK enhances p53 activity and affects expression downstream of p53. Interestingly, these functions of NLK are not related to its kinase activity. Consistent with these results, NLK-deficient cells have a resistance effect on DNA damage. Therefore, these findings emphasize that NLK is a novel factor in DDR mechanisms.Cell Death and Differentiation advance online publication, 13 June 2014; doi:10.1038/cdd.2014.78.