Sumoylation-deficient Prdx6 repairs aberrant Sumoylation-mediated Sp1 dysregulation-dependent Prdx6 repression and cell injury in aging and oxidative stress

Bhavana Chhunchha, Eri Kubo, Prerna Singh, Dhirendra P. Singh

Research output: Contribution to journalArticle

2 Scopus citations

Abstract

Progressive deterioration of antioxidant response in aging is a major culprit in the initiation of age-related pathobiology induced by oxidative stress. We previously reported that oxidative stress leads to a marked reduction in transcription factor Sp1 and its mediated Prdx6 expression in lens epithelial cells (LECs) leading to cell death. Herein, we examined how Sp1 activity goes awry during oxidative stress/aging, and whether it is remediable. We found that Sp1 is hyper-Sumoylated at lysine (K) 16 residue in aging LECs. DNA binding and promoter assays revealed, in aging and oxidative stress, a significant reduction in Sp1 overall binding, and specifically to Prdx6 promoter. Expression/overexpression assay revealed that the observed reduction in Sp1- DNA binding activity was connected to its hyper-Sumoylation due to increased reactive oxygen species (ROS) and Sumo1 levels, and reduced levels of Senp1, Prdx6 and Sp1. Mutagenesis of Sp1 at K16R (arginine) residue restored steady-state, and improved Sp1-DNA binding activity and transactivation potential. Extrinsic expression of Sp1K16R increased cell survival and reduced ROS levels by upregulating Prdx6 expression in LECs under aging/oxidative stress, demonstrating that Sp1K16R escapes the aberrant Sumoylation processes. Intriguingly, the deleterious processes are reversible by the delivery of Sumoylation-deficient Prdx6, an antioxidant, which would be a candidate molecule to restrict aging pathobiology.

Original languageEnglish (US)
Pages (from-to)2284-2315
Number of pages32
JournalAging
Volume10
Issue number9
DOIs
Publication statusPublished - Sep 1 2018

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Keywords

  • Antioxidant
  • Cell survival
  • Oxidative stress
  • Prdx6
  • Senp1
  • Sp1
  • Sumo1

ASJC Scopus subject areas

  • Aging
  • Cell Biology

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