DNA damage induces nuclear translocation of parkin

Parkin was first isolated as the candidate gene of autosomal recessive juvenile Parkinsonism (AR-JP) [1]. Although 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. In addition to its association with PD, parkin might be associated with carcinogenesis and may be a tumor suppressor [3]. 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]. Based on its structure, parkin may act as a docking station bringing substrate proteins to an E2 ubiquitin conjugating enzyme for ubiquitination, thus leading to their degradation [4]. Several parkin interacting proteins have been identified, including CDCrel-1 [5], glycosylated α-synuclein [6], synphilin-1 [7], PAEL-R [8], cyclin E [9], aminoacyl-tRNA synthetase cofactor p38 [10], and a PDZ containing protein CASK/Lin2 [11]. However, the mechanism by which parkin mutations cause PD remains to be determined.Accelerated DNA damage occurs during the aging of the human brain [12]. Furthermore, several studies suggest that DNA damage is involved in neurodegenerative processes [13,14]. For example, the level of the DNA damage marker, 8-hydroxyguanine is increased in genomic DNA in PD substantia nigra compared to non-PD controls [15]. In addition, somatic mitochondrial DNA mutations in cortex and substantia nigra are increased in PD [16]. Furthermore, it has been proposed that oxidative stress induced DNA damage could be an important risk factor for PD [17,18].These observations prompted us to examine genes associated with PD for a role in DNA damage response. The current studies provide evidence that DNA damage promotes nuclear translocation of parkin. These findings provide a potential interface between normal aging associated