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PMID: 18845680 Published · ppublish English Journal Article Research Support, N.I.H., Extramural

Role for proteasome activator PA200 and postglutamyl proteasome activity in genomic stability.

Proceedings of the National Academy of Sciences of the United States of America ·Vol. 105 ·No. 42 ·2008-10-21 ·Pages 16165-70

Blickwedehl J, Agarwal M, Seong C, Pandita RK, Melendy T, Sung P, Pandita TK, Bangia N

Abstract

Proteasome activator PA200 enhances proteasome-mediated cleavage after acidic residues in vitro; however, its role within cells is not known. Here, we show that, in response to ionizing radiation, PA200 forms hybrid proteasomes with 19S caps and 20S core proteasomes that accumulate on chromatin, leading to an increase in proteolytic activity. Unlike many other proteins that respond to DNA damage, the response of PA200 appears to be independent of Ataxia Telangiectasia Mutated and p53, but dependent on DNA-dependent protein kinase activity. Nonetheless, PA200 is critical because PA200-knockdown cells show genomic instability and reduced survival after exposure to ionizing radiation. This phenotype is reproduced by specific inhibition of postglutamyl activity of proteasomes, but combined treatment with PA200 siRNA and postglutamyl inhibitor does not show additive effects on survival. Together, these data suggest a unique role for PA200 in genomic stability that is likely mediated through its ability to enhance postglutamyl cleavage by proteasomes.

MeSH Terms
Animals Ataxia Telangiectasia Mutated Proteins Cell Cycle Proteins/genetics,metabolism Cell Line Cell Survival Chromatin/genetics Cricetinae DNA-Activated Protein Kinase/metabolism DNA-Binding Proteins/genetics,metabolism Genomic Instability/drug effects,genetics,radiation effects Glutamine/metabolism Humans Nuclear Proteins/metabolism Protease Inhibitors/pharmacology Proteasome Endopeptidase Complex/genetics,metabolism Proteasome Inhibitors Protein Binding Protein Serine-Threonine Kinases/genetics,metabolism Tumor Suppressor Protein p53/metabolism Tumor Suppressor Proteins/genetics,metabolism
Chemicals
Cell Cycle Proteins Chromatin DNA-Binding Proteins Nuclear Proteins Protease Inhibitors Proteasome Inhibitors Tumor Suppressor Protein p53 Tumor Suppressor Proteins Glutamine ATM protein, human Ataxia Telangiectasia Mutated Proteins DNA-Activated Protein Kinase Protein Serine-Threonine Kinases Proteasome Endopeptidase Complex
Authors & Affiliations
8 authors, click to expand affiliations / ORCID
Blickwedehl Jennifer
Department of Immunology, Roswell Park Cancer Institute, Buffalo, NY 14263.
Agarwal Manjula
Seong Changhyun
Pandita Raj K
Melendy Thomas
Sung Patrick
Pandita Tej K
Bangia Naveen
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Article Info
Journal
Proceedings of the National Academy of Sciences of the United States of America
Abbr.
Proc Natl Acad Sci U S A
ISSN
1091-6490
DOI
10.1073/pnas.0803145105
Published
2008-10-21
Epub
2008-00-09
Pages
16165-70
Language
English
Region
United States
NLM ID
7505876
PMCID
PMC2570974
Subset
IM
Grants
NCI NIH HHS · P30 CA016056 · United States
NCI NIH HHS · CA10445 · United States
NCI NIH HHS · CA123232 · United States
NCI NIH HHS · CA085183 · United States
NCI NIH HHS · R01 CA123232 · United States
NCI NIH HHS · T32 CA085183 · United States
NCI NIH HHS · CA016056 · United States
External Links
PubMed source DOI: 10.1073/pnas.0803145105 PMC Full Text View journal details
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