Mutations or inactivation of parkin, an E3 ubiquitin ligase, are associated with familial form or sporadic Parkinson＇s disease （PD）, respectively, which manifested with the selective vulnerability of neuronal ceils...Mutations or inactivation of parkin, an E3 ubiquitin ligase, are associated with familial form or sporadic Parkinson＇s disease （PD）, respectively, which manifested with the selective vulnerability of neuronal ceils in substantia nigra （SN） and striatum （STR） regions. However, the underlying molecular mechanism linking parkin with the etiology of PD remains elusive. Here we report that p62, a critical regulator for protein quality control, inclusion body formation, selective autophagy and diverse signaling pathways, is a new substrate of parkin. P62 levels were increased in the SN and STR regions, but not in other brain regions in parkin knockout mice. Parkin directly interacts with and ubiquitinates p62 at the K13 to promote proteasomal degradation of p62 even in the absence of ATG5. Pathogenic mutations, knockdown of parkin or mutation of p62 at K13 prevented the degradation of p62. We further showed that parkin deficiency mice have pronounced loss of tyrosine hydroxylase positive neurons and have worse performance in motor test when treated with 6-hydroxydopamine hydrochloride in aged mice. These results suggest that, in addition to their critical role in regulating autophagy, p62 are subjected to parkin mediated proteasomal degradation and implicate that the dysregulation of parkin/p62 axis may involve in the selective vulnerability of neuronal cells during the onset of PD pathogenesis.展开更多
Single-strand break repair protein poly(ADP-ribose)polymerase 1(PARP1)catalyzes the poly(ADPribosyl)ation of many key proteins in vivo and thus plays important roles in multiple DNA damage response pathways,rendering ...Single-strand break repair protein poly(ADP-ribose)polymerase 1(PARP1)catalyzes the poly(ADPribosyl)ation of many key proteins in vivo and thus plays important roles in multiple DNA damage response pathways,rendering it a promising target in cancer therapy.The tumor-suppressor effects of PARP inhibitors have attracted significant interest for development of novel cancer therapies.However,recent evidence indicated that the underlying mechanism of PARP inhibitors in tumor therapy is more complex than previously expected.The present review will focus on recent progress on the role of PARP1 in the DNA damage response and PARP inhibitors in cancer therapy.The emerging resistance of BRCA-deficient tumors to PARP inhibitors is also briefly discussed from the perspective of DNA damage and repair.These recent research advances will inform the selection of patient populations who can benefit from the PARP inhibitor treatment and development of effective drug combination strategies.展开更多
基金We are grateful to Drs. Ted Dawson and Jian Feng for generously providing the plasmids. We are also grateful to Professor Mark Bartlam from Nankai University, Tianjin, China for a critical reading of the manuscript. The research was supported by the National Basic Research Program （973 Program） （No. 2011 CB910903） from MOST and project （Grant Nos. 81130045, 31471300, 31271529, 301520103904） from the National Natural Science Foundation of China.
文摘Mutations or inactivation of parkin, an E3 ubiquitin ligase, are associated with familial form or sporadic Parkinson＇s disease （PD）, respectively, which manifested with the selective vulnerability of neuronal ceils in substantia nigra （SN） and striatum （STR） regions. However, the underlying molecular mechanism linking parkin with the etiology of PD remains elusive. Here we report that p62, a critical regulator for protein quality control, inclusion body formation, selective autophagy and diverse signaling pathways, is a new substrate of parkin. P62 levels were increased in the SN and STR regions, but not in other brain regions in parkin knockout mice. Parkin directly interacts with and ubiquitinates p62 at the K13 to promote proteasomal degradation of p62 even in the absence of ATG5. Pathogenic mutations, knockdown of parkin or mutation of p62 at K13 prevented the degradation of p62. We further showed that parkin deficiency mice have pronounced loss of tyrosine hydroxylase positive neurons and have worse performance in motor test when treated with 6-hydroxydopamine hydrochloride in aged mice. These results suggest that, in addition to their critical role in regulating autophagy, p62 are subjected to parkin mediated proteasomal degradation and implicate that the dysregulation of parkin/p62 axis may involve in the selective vulnerability of neuronal cells during the onset of PD pathogenesis.
基金supported by National Natural Science Foundation of China(Grant Nos.30970588 and 31170730[C.G],Grant No.30970931[T.S.T])“One-Hundred-Talent Program”(C.G)and“Knowledge Innovation Program KSCX2-YW-R-148”(T.S.T)from Chinese Academy of Sciences,and National Basic Research Program of China(Nos.2011CB944302,2011CB965003,2012CB944702).
文摘Single-strand break repair protein poly(ADP-ribose)polymerase 1(PARP1)catalyzes the poly(ADPribosyl)ation of many key proteins in vivo and thus plays important roles in multiple DNA damage response pathways,rendering it a promising target in cancer therapy.The tumor-suppressor effects of PARP inhibitors have attracted significant interest for development of novel cancer therapies.However,recent evidence indicated that the underlying mechanism of PARP inhibitors in tumor therapy is more complex than previously expected.The present review will focus on recent progress on the role of PARP1 in the DNA damage response and PARP inhibitors in cancer therapy.The emerging resistance of BRCA-deficient tumors to PARP inhibitors is also briefly discussed from the perspective of DNA damage and repair.These recent research advances will inform the selection of patient populations who can benefit from the PARP inhibitor treatment and development of effective drug combination strategies.
