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

Jennifer Blickwedehl, Manjula Agarwal, Changhyun Seong, Raj K. Pandita, Thomas Melendy, Patrick Sung, Tej K. Pandita, Naveen Bangia

Research output: Contribution to journalArticle

66 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)16165-16170
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume105
Issue number42
DOIs
StatePublished - Oct 21 2008
Externally publishedYes

Keywords

  • ATM
  • Chromatin
  • DNA damage
  • DNA-dependent protein kinase
  • Ionizing radiation

ASJC Scopus subject areas

  • General

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