CDK1 dependent phosphorylation of hTERT contributes to cancer progression.

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.

Citation

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, Kenkichi Masutomi. CDK1 dependent phosphorylation of hTERT contributes to cancer progression. Nature communications. 2020 Mar 25;11(1):1557

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PMID: 32214089

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