title: Proliferating cell nuclear antigen binds DNA polymerase-β and mediates 1-methyl-4-phenylpyridinium-induced neuronal death.
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.
authors.affiliation: Department of Neurology, Renmin Hospital of Wuhan University, Wuhan, China.
authors.forename: Zhentao
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: Department of Neurology, Renmin Hospital of Wuhan University, Wuhan, China.
authors.forename: Zhaohui
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: Department of Neurology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
authors.forename: Hongcai
authors.initials: H
authors.lastname: Wang
authors.affiliation: Department of Neurology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
authors.forename: Guoxin
authors.initials: G
authors.lastname: Zhang
authors.affiliation: Department of Neurology, Renmin Hospital of Wuhan University, Wuhan, China.
authors.forename: Dan
authors.initials: D
authors.lastname: Hu
authors.affiliation: Department of Neurology, Renmin Hospital of Wuhan University, Wuhan, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Xiong
authors.affiliation: Department of Neurology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
authors.forename: Nian
authors.initials: N
authors.lastname: Xiong
authors.affiliation: Department of Neurology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
authors.forename: Tao
authors.initials: T
authors.lastname: Wang
authors.affiliation: Department of Neurology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
authors.forename: Xuebing
authors.initials: X
authors.lastname: Cao
authors.affiliation: Department of Neurology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
authors.forename: Ling
authors.initials: L
authors.lastname: Mao
mesh_terms: D015655:1-Methyl-4-phenylpyridinium / Q000494:pharmacology; D000818:Animals; D016923:Cell Death / Q000187:drug effects* / Q000235:genetics; D002455:Cell Division / Q000187:drug effects; D019951:DNA Polymerase beta / Q000235:genetics / Q000378:metabolism*; D004261:DNA Replication / Q000187:drug effects / Q000235:genetics; D059290:Dopaminergic Neurons / Q000187:drug effects / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D010300:Parkinson Disease / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D018809:Proliferating Cell Nuclear Antigen / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding / Q000235:genetics; D013378:Substantia Nigra / Q000378:metabolism / Q000473:pathology
chemical_list: D018809:Proliferating Cell Nuclear Antigen; D019951:DNA Polymerase beta; D015655:1-Methyl-4-phenylpyridinium