The Catalytic Subunit of DNA-Dependent Protein Kinase Coordinates with Polo-Like Kinase 1 to Facilitate Mitotic Entry.
DNA-dependent protein kinase catalytic subunit (DNA-PKcs) is the key regulator of the non-homologous end joining pathway of DNA double-strand break repair. We have previously reported that DNA-PKcs is required for maintaining chromosomal stability and mitosis progression. Our further investigations reveal that deficiency in DNA-PKcs activity caused a delay in mitotic entry due to dysregulation of cyclin-dependent kinase 1 (Cdk1), the key driving force for cell cycle progression through G2/M transition. Timely activation of Cdk1 requires polo-like kinase 1 (Plk1), which affects modulators of Cdk1. We found that DNA-PKcs physically interacts with Plk1 and could facilitate Plk1 activation both in vitro and in vivo. Further, DNA-PKcs-deficient cells are highly sensitive to Plk1 inhibitor BI2536, suggesting that the coordination between DNA-PKcs and Plk1 is not only crucial to ensure normal cell cycle progression through G2/M phases but also required for cellular resistance to mitotic stress. On the basis of the current study, it is predictable that combined inhibition of DNA-PKcs and Plk1 can be employed in cancer therapy strategy for synthetic lethality.
Division of Molecular Radiation Biology, Department of Radiation Oncology, University of Texas Southwestern Medical Center, Dallas, TX, USA.
Kyung-Jong
KJ
Lee
Division of Molecular Radiation Biology, Department of Radiation Oncology, University of Texas Southwestern Medical Center, Dallas, TX, USA; Department of Radiobiology, School of Radiation Medicine and Protection, Medical College of Soochow University, School for Radiological and Interdisciplinary Sciences, Suzhou, Jiangsu, China.
Zeng-Fu
ZF
Shang
Division of Molecular Radiation Biology, Department of Radiation Oncology, University of Texas Southwestern Medical Center, Dallas, TX, USA.
Yu-Fen
YF
Lin
Division of Molecular Radiation Biology, Department of Radiation Oncology, University of Texas Southwestern Medical Center, Dallas, TX, USA.
Jingxin
J
Sun
Division of Molecular Radiation Biology, Department of Radiation Oncology, University of Texas Southwestern Medical Center, Dallas, TX, USA.
Keiko
K
Morotomi-Yano
Division of Molecular Radiation Biology, Department of Radiation Oncology, University of Texas Southwestern Medical Center, Dallas, TX, USA.
Debabrata
D
Saha
Division of Molecular Radiation Biology, Department of Radiation Oncology, University of Texas Southwestern Medical Center, Dallas, TX, USA. Electronic address: Benjamin.chen@utsouthwestern.edu.
Benjamin P C
BP
Chen
D016203:CDC2 Protein Kinase; D018797:Cell Cycle Proteins / Q000378:metabolism*; D002455:Cell Division / Q000187:drug effects / Q000235:genetics; D045744:Cell Line, Tumor; D018844:Cyclin-Dependent Kinases / Q000378:metabolism; D053903:DNA Breaks, Double-Stranded / Q000187:drug effects; D051747:DNA-Activated Protein Kinase / Q000378:metabolism*; D016195:G2 Phase / Q000187:drug effects / Q000235:genetics; D045325:HCT116 Cells; D006367:HeLa Cells; D006801:Humans; D008938:Mitosis / Q000187:drug effects / Q000235:genetics*; D009687:Nuclear Proteins / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D011621:Pteridines / Q000494:pharmacology; D000097869:Polo-Like Kinase 1
D016203:CDC2 Protein Kinase; D018797:Cell Cycle Proteins; D018844:Cyclin-Dependent Kinases; D051747:DNA-Activated Protein Kinase; D009687:Nuclear Proteins; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D011621:Pteridines; D000097869:Polo-Like Kinase 1; C518477:BI 2536; C497263:PRKDC protein, human; C528899:CDK1 protein, human