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