DNA damage induces nuclear translocation of parkin

Shyan-Yuan Kao

doi:10.1186/1423-0127-16-67

Abstract

Parkinson's disease (PD) is the second most common form of human degenerative disorder. Mutation of parkin is one of the most prevalent causes of autosomal recessive PD. Parkin is an E3 ubiquitin ligase that acts on a variety of substrates, resulting in polyubiquitination and degradation by the proteasome or monoubiquitination and regulation of biological activity. However, the cellular functions of parkin that relate to its pathological involvement in PD are not well understood. Here I show that parkin translocates into nucleus upon DNA damage. Nuclear translocation of parkin appears to be required to promote DNA repair. These findings suggest that DNA damage induces nuclear translocation of parkin leading to the PCNA interaction and possibly other nuclear proteins involved in DNA repair. These results suggest that parkin promotes DNA repair and protects against genotoxicity, and implicate DNA damage as a potential pathogenic mechanism in parkinsonism.

Highlights

Parkin was first isolated as the candidate gene of autosomal recessive juvenile Parkinsonism (AR-JP) [1]
Ing that nuclear localized parkin is indispensable for the regulation of DNA repair activity. These findings suggest that a broad range of DNA damaging agents induce nuclear translocation of parkin, including hydrogen peroxide, which induces oxidative base damage, UV irradiation, which induces pyrimidine dimer formation, and etoposide, which induces DNA double strand breaks
It has been shown that parkin-deficient mice show increased 8-oxoguanine in cerebral cortex, and parkin promotes both base and nucleotide excision repair in cultured cells [24]

Summary

Introduction

Parkin was first isolated as the candidate gene of autosomal recessive juvenile Parkinsonism (AR-JP) [1]. Many types of mutations, such as point mutations, truncations and/or splicing variants of parkin, are found in Parkinson's disease (PD) patients [2], the mechanism of how parkin is involved in PD remains elusive. Abnormal parkin transcripts have been detected in a number of different tumor cell types, including lung, cervical, pancreatic, and kidney tumors [3]. Parkin functions as an E3 ubiquitin protein ligase [1]. Parkin may act as a docking station bringing substrate proteins to an E2 ubiquitin conjugating enzyme for ubiquitination, leading to their degradation [4]. The mechanism by which parkin mutations cause PD remains to be determined

Methods

Results

Conclusion