Proliferating cell nuclear antigen binds DNA polymerase-β and mediates 1-methyl-4-phenylpyridinium-induced neuronal death

Zhentao Zhang; Zhaohui Zhang; Hongcai Wang; Guoxin Zhang; Dan Hu; Jing Xiong; Nian Xiong; Tao Wang; Xuebing Cao; Ling Mao

doi:10.1371/journal.pone.0106669

Proliferating cell nuclear antigen binds DNA polymerase-β and mediates 1-methyl-4-phenylpyridinium-induced neuronal death

PLoS One. 2014 Sep 3;9(9):e106669. doi: 10.1371/journal.pone.0106669. eCollection 2014.

Authors

Affiliations

¹ Department of Neurology, Renmin Hospital of Wuhan University, Wuhan, China.
² Department of Neurology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.

Abstract

The mechanisms leading to dopaminergic neuronal loss in the substantia nigra of patients with Parkinson disease (PD) remain poorly understood. We recently reported that aberrant DNA replication mediated by DNA polymerase-β (DNA pol-β) plays a causal role in the death of postmitotic neurons in an in vitro model of PD. In the present study, we show that both proliferating cell nuclear antigen (PCNA) and DNA pol-β are required for MPP(+)-induced neuronal death. PCNA binds to the catalytic domain of DNA pol-β in MPP(+)-treated neurons and in post-mortem brain tissues of PD patients. The PCNA-DNA pol-β complex is loaded into DNA replication forks and mediates DNA replication in postmitotic neurons. The aberrant DNA replication mediated by the PCNA-DNA pol-β complex induces p53-dependent neuronal cell death. Our results indicate that the interaction of PCNA and DNA pol-β contributes to neuronal death in PD.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

1-Methyl-4-phenylpyridinium / pharmacology
Animals
Cell Death / drug effects*
Cell Death / genetics
Cell Division / drug effects
DNA Polymerase beta / genetics
DNA Polymerase beta / metabolism*
DNA Replication / drug effects
DNA Replication / genetics
Dopaminergic Neurons / drug effects
Dopaminergic Neurons / metabolism
HEK293 Cells
Humans
Mice
Mice, Knockout
Parkinson Disease / genetics
Parkinson Disease / metabolism*
Parkinson Disease / pathology
Proliferating Cell Nuclear Antigen / genetics
Proliferating Cell Nuclear Antigen / metabolism*
Protein Binding / genetics
Substantia Nigra / metabolism
Substantia Nigra / pathology

Substances

Proliferating Cell Nuclear Antigen
DNA Polymerase beta
1-Methyl-4-phenylpyridinium

Grants and funding

This study was supported by National Natural Science Foundation of China (Grant no. 81100958, ZZ and 81101905, LM), Doctoral Fund of Ministry of Education of China (http://www.cutech.edu.cn/, Grant no. 20110141120061, ZZ), and Natural Science Foundation of Hubei Provence (http://www.hbstd.gov.cn/, Grant no. 2011CBD480, ZZ). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.