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Wss1 metalloprotease partners with Cdc48/Doa1 in processing genotoxic SUMO conjugates

Maxim Y Balakirev1, James E Mullally2, Adrien Favier3

  • 1Institut de recherches en technologies et sciences pour le vivant-Biologie à Grande Echelle, Commissariat a l'Energie Atomique et aux Energies Alternatives (CEA), Grenoble, France.

Elife
|September 9, 2015
PubMed

Insights

The metalloprotease Wss1, crucial for DNA repair, clears sumoylated proteins during genotoxic stress. It forms a complex that extends SUMO chains, aiding cell survival and protein complex clearance.

Area of Science:

  • Molecular Biology
  • Cellular Biology
  • Biochemistry

Background:

  • Sumoylation regulates DNA repair complex composition during genotoxic stress.
  • The yeast metalloprotease Wss1 and its mammalian homolog DVC1/Spartan are key in managing sumoylated proteins.
  • Wss1 activity is controlled by a cysteine switch mechanism, sensitive to chemical stress and DNA binding.

Purpose of the Study:

  • To investigate the role of Wss1 in DNA repair and protein complex regulation under genotoxic stress.
  • To elucidate the mechanism of Wss1-mediated clearance of sumoylated proteins.
  • To explore the connection between Wss1, SUMOylation, and cellular stress response pathways.

Main Methods:

  • Analysis of Wss1's proteolytic activity and regulation.
  • Investigating the Wss1/Cdc48/Doa1 complex formation and function.
  • Assessing cell survival following DNA damage in Wss1-dependent pathways.
  • Studying the role of Wss1 in the absence of Tdp1.

Main Results:

  • Wss1 is essential for cell survival after UV irradiation and in response to camptothecin-induced topoisomerase complexes.
  • Wss1, in complex with Cdc48 and Doa1, exhibits SUMO ligase activity, extending SUMO chains on target proteins.
  • Wss1 activation leads to self-cleavage and proteolysis of associated proteins, facilitating clearance.
  • In Tdp1-deficient cells, topoisomerase complex clearance is dependent on SUMOylation and Wss1.
  • Wss1 localization to vacuoles upon genotoxic stress suggests a link to autophagy via the Doa1 adapter.

Conclusions:

  • Wss1 plays a critical role in DNA repair by clearing sumoylated proteins and regulating protein complexes.
  • The Wss1/Cdc48/Doa1 complex possesses novel SUMO ligase activity, contributing to stress response.
  • Wss1 activation and subsequent proteolysis are key events in DNA damage resolution.
  • Genotoxic stress, Wss1, and autophagy are interconnected, potentially mediated by the Doa1 adapter.
Keywords:
Cdc48DNA repairDoa1S. cerevisiaeSUMO metabolismbiochemistrycell biologypoly SUMOvacuole

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