Regulation and functional contribution of thymidine kinase 1 in repair of DNA damage
Journal
Journal of Biological Chemistry
Journal Volume
285
Journal Issue
35
Pages
27327-27335
Date Issued
2010
Author(s)
Abstract
Cellular supply of dNTPs is essential in the DNA replication and repair processes. Here we investigated the regulation of thymidine kinase 1 (TK1) in response to DNA damage and found that genotoxic insults in tumor cells cause up-regulation and nuclear localization of TK1. During recovery from DNA damage, TK1 accumulates in p53-null cells due to a lack of mitotic proteolysis as these cells are arrested in the G2 phase by checkpoint activation. We show that in p53-proficient cells, p21 expression in response to DNA damage prohibits G1/S progression, resulting in a smaller G2 fraction and less TK1 accumulation. Thus, the p53 status of tumor cells affects the level of TK1 after DNA damage through differential cell cycle control. Furthermore, it was shown that in HCT-116 p53-/- cells, TK1 is dispensable for cell proliferation but crucial for dTTP supply during recovery from DNA damage, leading to better survival. Depletion of TK1 decreases the efficiency of DNA repair during recovery from DNA damage and generates more cell death. Altogether, our data suggest that more dTTP synthesis via TK1 take place after genotoxic insults in tumor cells, improving DNA repair during G2 arrest. ? 2010 by The American Society for Biochemistry and Molecular Biology, Inc.
SDGs
Other Subjects
Cell cycle control; Checkpoint activation; DNA damages; DNA repair; DNA replications; Genotoxic; Nuclear localization; Repair process; Thymidine kinase; Tumor cells; Up-regulation; Cell death; Cell proliferation; Genes; Recovery; Repair; Tumors; DNA; protein p21; protein p53; thymidine kinase 1; thymidine triphosphate; apoptosis; article; cancer cell culture; cell cycle arrest; cell cycle G2 phase; cell cycle progression; cell cycle regulation; cell cycle S phase; cell proliferation; cell strain HCT116; controlled study; cytotoxicity; DNA damage; DNA repair; enzyme localization; enzyme regulation; mitosis; priority journal; protein degradation; protein expression; tumor cell; upregulation; Cell Line, Tumor; Cyclin-Dependent Kinase Inhibitor p21; DNA Damage; DNA Repair; DNA Replication; Humans; Interphase; Neoplasms; Thymidine Kinase; Thymine Nucleotides; Tumor Suppressor Protein p53
Type
journal article