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PCNA dependent cellular activities tolerate dramatic perturbations in PCNA client interactions.

Rosemary H C Wilson1, Antonio J Biasutto2, Lihao Wang1

  • 1Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford, OX3 7BN, UK.

DNA Repair
|January 12, 2017
PubMed
Summary
This summary is machine-generated.

The PCNAS228I mutation impairs DNA repair cofactor interactions, causing subtle cellular defects in undamaged cells and contributing to PCNA-associated DNA repair disorder (PARD).

Keywords:
DNA repairDNA replicationPCNAPCNA-associated repair disorder (PARD)

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Area of Science:

  • Molecular Biology
  • Genetics
  • Biochemistry

Background:

  • Proliferating cell nuclear antigen (PCNA) is crucial for DNA replication and repair, acting as a cofactor that recruits other proteins.
  • PCNA-associated DNA repair disorder (PARD) is linked to a specific mutation, PCNAS228I, affecting cellular function even in undamaged cells.

Purpose of the Study:

  • To investigate the functional consequences of the PCNAS228I mutation on PCNA's interactions with its binding partners.
  • To understand how these altered interactions contribute to the cellular defects observed in PARD.

Main Methods:

  • Analysis of binding affinities between wild-type PCNA, PCNAS228I, and various PCNA-interacting proteins (PIPs).
  • Assessment of protein stability (p21, Cdt1) in cells from PARD-affected individuals.
  • Evaluation of PCNA ubiquitination and structural changes in the inter-domain connecting loop.

Main Results:

  • The PCNAS228I mutation significantly reduces binding to most PCNA-interacting proteins (PIPs), including Cdt1, DNMT1, PolD3p66, and PolD4p12.
  • The p21 PIP box retains binding to PCNAS228I, independent of other p21 sequences.
  • Despite reduced in vitro binding, p21 and Cdt1 stability in PARD cells showed only minor alterations, with PCNA ubiquitination unaffected.

Conclusions:

  • The PCNAS228I mutation leads to reduced affinity for specific PCNA-interacting proteins.
  • These altered interactions cause subtle cellular defects in undamaged cells, contributing to the etiology of PCNA-associated DNA repair disorder (PARD).
  • The p21 PIP box sequence is sufficient for binding to the mutated PCNAS228I.