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Structurally distinct ubiquitin- and sumo-modified PCNA: implications for their distinct roles in the DNA damage

Susan E Tsutakawa1, Chunli Yan2, Xiaojun Xu2

  • 1Life Sciences Division, Lawrence Berkeley National Laboratory, Berkeley, CA, 94720 USA.

Structure (London, England : 1993)
|March 17, 2015
PubMed

Insights

Posttranslational modifications of proliferating cell nuclear antigen (PCNA) by SUMO and ubiquitin alter DNA repair. These modifiers bind PCNA differently, impacting cellular responses to DNA damage and tolerance pathways.

Area of Science:

  • Molecular Biology
  • Structural Biology
  • Biochemistry

Background:

  • Proliferating cell nuclear antigen (PCNA) is crucial for DNA replication and cellular responses to DNA damage.
  • Posttranslational modifications, specifically SUMOylation and ubiquitination, regulate PCNA's functions.
  • The precise mechanisms by which these modifications impact DNA repair and damage tolerance pathways remain largely unelucidated.

Purpose of the Study:

  • To determine the atomic models of PCNA modified by ubiquitin (PCNA-Ub) and SUMO (PCNA-SUMO).
  • To elucidate the distinct binding modes and conformational behaviors of SUMO and ubiquitin on PCNA.
  • To understand how these structural differences influence PCNA-dependent DNA repair and damage tolerance.

Main Methods:

  • Utilized hybrid methods combining atomic modeling with small-angle X-ray scattering (SAXS) data.
  • Analyzed solution structures of PCNAK107-Ub and PCNAK164-SUMO complexes.
  • Investigated the electrostatic potentials of SUMO and ubiquitin to explain binding differences.

Main Results:

  • Identified distinct association modes for SUMO and ubiquitin with PCNA.
  • Ubiquitin was observed to adopt discrete, docked binding positions on PCNA.
  • SUMO exhibited a tethering association, resulting in extended and flexible conformations, attributed to opposing electrostatic potentials.

Conclusions:

  • SUMO and ubiquitin display fundamentally different binding mechanisms and conformational impacts on PCNA.
  • These structural variations likely affect PCNA's interactions with partner proteins and accessibility for regulatory processes.
  • The findings provide critical insights into the regulation of DNA repair and damage tolerance pathways by PCNA modification.

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