Nuclear PGK1 Alleviates ADP-Dependent Inhibition of CDC7 to Promote DNA Replication

Xinjian Li; Xu Qian; Hongfei Jiang; Yan Xia; Yanhua Zheng; Jing Li; Bi-Jun Huang; Jing Fang; Chao-Nan Qian; Tao Jiang; Yi-Xin Zeng; Zhimin Lu

doi:10.1016/j.molcel.2018.09.007

Nuclear PGK1 Alleviates ADP-Dependent Inhibition of CDC7 to Promote DNA Replication

Mol Cell. 2018 Nov 15;72(4):650-660.e8. doi: 10.1016/j.molcel.2018.09.007. Epub 2018 Nov 1.

Authors

Xinjian Li¹, Xu Qian², Hongfei Jiang³, Yan Xia⁴, Yanhua Zheng⁴, Jing Li³, Bi-Jun Huang⁵, Jing Fang⁶, Chao-Nan Qian⁵, Tao Jiang³, Yi-Xin Zeng⁷, Zhimin Lu⁸

Affiliations

¹ Brain Tumor Center, Department of Neuro-Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; CAS Key Laboratory of Infection and Immunity, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China.
² Brain Tumor Center, Department of Neuro-Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Personalized Medicine, School of Public Health, Nanjing Medical University, Nanjing 211166, China.
³ Qingdao National Laboratory for Marine Science and Technology, Key Laboratory of Marine Drugs of Minister of Education of China, School of Medicine and Pharmacy, Ocean University of China, Qingdao 266003, China.
⁴ Brain Tumor Center, Department of Neuro-Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
⁵ State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-Sen University Cancer Center, Guangzhou 510060, China.
⁶ Cancer Institute, The Affiliated Hospital of Qingdao University, Qingdao, Shandong 266061, China; Qingdao Cancer Institute, Qingdao, Shandong 266061, China.
⁷ CAS Key Laboratory of Infection and Immunity, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China; State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-Sen University Cancer Center, Guangzhou 510060, China.
⁸ Brain Tumor Center, Department of Neuro-Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; Cancer Biology Program, MD Anderson Cancer Center UT Health Graduate School of Biomedical Sciences, The University of TX, Houston, Texas 77030, USA. Electronic address: zlumdacc@yahoo.com.

PMID: 30392930
DOI: 10.1016/j.molcel.2018.09.007

Abstract

DNA replication is initiated by assembly of the kinase cell division cycle 7 (CDC7) with its regulatory activation subunit, activator of S-phase kinase (ASK), to activate DNA helicase. However, the mechanism underlying regulation of CDC7-ASK complex is unclear. Here, we show that ADP generated from CDC7-mediated MCM phosphorylation binds to an allosteric region of CDC7, disrupts CDC7-ASK interaction, and inhibits CDC7-ASK activity in a feedback way. EGFR- and ERK-activated casein kinase 2α (CK2α) phosphorylates nuclear phosphoglycerate kinase (PGK) 1 at S256, resulting in interaction of PGK1 with CDC7. CDC7-bound PGK1 converts ADP to ATP, thereby abrogating the inhibitory effect of ADP on CDC7-ASK activity, promoting the recruitment of DNA helicase to replication origins, DNA replication, cell proliferation, and brain tumorigenesis. These findings reveal an instrumental self-regulatory mechanism of CDC7-ASK activity by its kinase reaction product ADP and a nonglycolytic role for PGK1 in abrogating this negative feedback in promoting tumor development.

Keywords: ADP; ASK; CDC7; CK2α; DNA replication; EGFR; ERK1/2; PGK1; phosphorylation; tumorigenesis.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Adenosine Diphosphate / metabolism*
Animals
Casein Kinase II / genetics
Casein Kinase II / metabolism*
Cell Cycle Proteins / antagonists & inhibitors*
Cell Cycle Proteins / genetics
Cell Cycle Proteins / metabolism
Cell Cycle Proteins / physiology
Cell Line
Cell Line, Tumor
DNA Helicases / genetics
DNA Helicases / metabolism
DNA Replication*
Female
Heterografts
Humans
MAP Kinase Signaling System
Mice
Mice, Inbred BALB C
Mice, Nude
Phosphoglycerate Kinase / genetics
Phosphoglycerate Kinase / metabolism*
Phosphorylation
Protein Binding
Protein Serine-Threonine Kinases / antagonists & inhibitors*
Protein Serine-Threonine Kinases / genetics
Protein Serine-Threonine Kinases / metabolism
Protein Serine-Threonine Kinases / physiology
Replication Origin

Substances

Cell Cycle Proteins
DBF4 protein, human
Adenosine Diphosphate
CDC7 protein, human
Casein Kinase II
Protein Serine-Threonine Kinases
PGK1 protein, human
Phosphoglycerate Kinase
DNA Helicases

Abstract

Publication types

MeSH terms

Substances

Grants and funding