CDK1 dependent phosphorylation of hTERT contributes to cancer progression

Mami Yasukawa, Yoshinari Ando, Taro Yamashita, Yoko Matsuda, Shisako Shoji, Masaki Suimye Morioka, Hideya Kawaji, Kumiko Shiozawa, Mitsuhiro Machitani, Takaya Abe, Shinji Yamada, Mika K. Kaneko, Yukinari Kato, Yasuhide Furuta, Tadashi Kondo, Mikako Shirouzu, Yoshihide Hayashizaki, Shuichi Kaneko and Kenkichi Masutomi ()
Additional contact information
Mami Yasukawa: National Cancer Center Research Institute
Yoshinari Ando: National Cancer Center Research Institute
Taro Yamashita: Kanazawa University Graduate School of Medical Science
Yoko Matsuda: Tokyo Metropolitan Geriatric Hospital and Institute of Gerontology
Shisako Shoji: RIKEN Center for Biosystems Dynamics Research
Masaki Suimye Morioka: RIKEN Center for Integrative Medical Sciences
Hideya Kawaji: RIKEN Center for Integrative Medical Sciences
Kumiko Shiozawa: National Cancer Center Research Institute
Mitsuhiro Machitani: National Cancer Center Research Institute
Takaya Abe: RIKEN Center for Life Science Technologies
Shinji Yamada: Tohoku University Graduate School of Medicine
Mika K. Kaneko: Tohoku University Graduate School of Medicine
Yukinari Kato: Tohoku University Graduate School of Medicine
Yasuhide Furuta: RIKEN Center for Life Science Technologies
Tadashi Kondo: National Cancer Center Research Institute
Mikako Shirouzu: RIKEN Center for Biosystems Dynamics Research
Yoshihide Hayashizaki: RIKEN Preventive Medicine and Diagnosis Innovation Program
Shuichi Kaneko: Kanazawa University Graduate School of Medical Science
Kenkichi Masutomi: National Cancer Center Research Institute

Nature Communications, 2020, vol. 11, issue 1, 1-18

Abstract: 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 reveal that phosphorylation of hTERT at threonine 249 occurs more frequently in aggressive cancers. Using CRISPR/Cas9 genome editing, we introduce substitution mutations at threonine 249 in the endogenous hTERT locus and find that phosphorylation of threonine 249 is necessary for hTERT-mediated RNA dependent RNA polymerase (RdRP) activity but dispensable for reverse transcriptase and terminal transferase activities. Cap Analysis of Gene Expression (CAGE) demonstrates 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 telomere independent manner.

Date: 2020
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DOI: 10.1038/s41467-020-15289-7

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