TY - JOUR
T1 - CDK1 dependent phosphorylation of hTERT contributes to cancer progression
AU - Yasukawa, Mami
AU - Ando, Yoshinari
AU - Yamashita, Taro
AU - Matsuda, Yoko
AU - Shoji, Shisako
AU - Morioka, Masaki Suimye
AU - Kawaji, Hideya
AU - Shiozawa, Kumiko
AU - Machitani, Mitsuhiro
AU - Abe, Takaya
AU - Yamada, Shinji
AU - Kaneko, Mika K.
AU - Kato, Yukinari
AU - Furuta, Yasuhide
AU - Kondo, Tadashi
AU - Shirouzu, Mikako
AU - Hayashizaki, Yoshihide
AU - Kaneko, Shuichi
AU - Masutomi, Kenkichi
N1 - Funding Information:
was supported in part by the Grant-in-Aid for challenging Exploratory Research under Grant Number 15K14482, AMED under Grant Number JP18fk0210005, The National Cancer Center Research and Development Fund (30-A-4), Daiichi Sankyo Foundation of Life Science to K.M. and the Platform Project for Supporting Drug Discovery and Life Science Research (Basis for Supporting Innovative Drug Discovery and Life Science Research [BINDS]) from AMED under Grant Number JP17am0101078 to Y.K.
Publisher Copyright:
© 2020, The Author(s).
PY - 2020/12/1
Y1 - 2020/12/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85082508585&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85082508585&partnerID=8YFLogxK
U2 - 10.1038/s41467-020-15289-7
DO - 10.1038/s41467-020-15289-7
M3 - Article
C2 - 32214089
AN - SCOPUS:85082508585
SN - 2041-1723
VL - 11
JO - Nature Communications
JF - Nature Communications
IS - 1
M1 - 1557
ER -
