CDK1 dependent phosphorylation of hTERT contributes to cancer progression

Mami Yasukawa, Yoshinari Ando, Taro Yamashita, Yoko Matsuda, Shisako Shoji, Masaki S. Morioka, Hideya Kawaji, Kumiko Shiozawa, Takaya Abe, Shinji Yamada, Mika K. Kaneko, Yukinari Kato, Yasuhide Furuta, Tadashi Kondo, Mikako Shirouzu, Yoshihide Hayashizaki, Shuichi Kaneko, Kenkichi Masutomi

Research output: Contribution to journalArticlepeer-review

Abstract

The telomerase reverse transcriptase is upregulated in the majority of human cancers and contributes directly to cell transformation. Here we report that hTERT is phosphorylated at threonine 249 during mitosis by the serine/threonine kinase CDK1. Clinicopathological analyses revealed that phosphorylation of hTERT at threonine 249 occurs more frequently in advanced cancers. Using CRISPR/Cas9 genome editing, we introduced substitution mutations at threonine 249 in the endogenous hTERT locus and found that phosphorylation of threonine 249 is necessary for hTERT-mediated RNA dependent RNA polymerase (RdRP) activity but dispensable for reverse transcriptase activity. Cap Analysis of Gene Expression (CAGE) demonstrated that hTERT phosphorylation at 249 regulates the expression of specific genes that are necessary for cancer cell proliferation and tumor formation. These observations indicate that phosphorylation at threonine 249 regulates hTERT RdRP and contributes to cancer progression in a telomerase independent manner.

Original languageEnglish
JournalUnknown Journal
DOIs
Publication statusPublished - 2019 Feb 21

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)
  • Immunology and Microbiology(all)
  • Neuroscience(all)
  • Pharmacology, Toxicology and Pharmaceutics(all)

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