A thermosensitive PCNA allele underlies an ataxia-telangiectasia-like disorder

Proliferating cell nuclear antigen (PCNA) is a sliding clamp protein that coordinates DNA replication with various DNA maintenance events that are critical for human health. Recently, a hypomorphic homozygous serine to isoleucine (S228I) substitution in PCNA was described to underlie a rare DNA repa...

Full description

Saved in:
Bibliographic Details
Published in:The Journal of biological chemistry 2023-05, Vol.299 (5), p.104656-104656, Article 104656
Main Authors: Magrino, Joseph, Munford, Veridiana, Martins, Davi Jardim, Homma, Thais K., Page, Brendan, Gaubitz, Christl, Freire, Bruna L., Lerario, Antonio M., Vilar, Juliana Brandstetter, Amorin, Antonio, Leão, Emília K.E., Kok, Fernando, Menck, Carlos FM, Jorge, Alexander AL, Kelch, Brian A.
Format: Article
Language:English
Subjects:
Alleles
Ataxia Telangiectasia - genetics
Ataxia Telangiectasia - metabolism
Chromatin - genetics
Chromatin - metabolism
Collection: Molecular Bases of Disease
crystal structure
DNA damage repair
DNA Repair - genetics
DNA Replication
Humans
PCNA
Proliferating Cell Nuclear Antigen - chemistry
Proliferating Cell Nuclear Antigen - genetics
Proliferating Cell Nuclear Antigen - metabolism
Protein Binding - genetics
Protein Stability
rare disease
Substrate Specificity
Temperature
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:Proliferating cell nuclear antigen (PCNA) is a sliding clamp protein that coordinates DNA replication with various DNA maintenance events that are critical for human health. Recently, a hypomorphic homozygous serine to isoleucine (S228I) substitution in PCNA was described to underlie a rare DNA repair disorder known as PCNA-associated DNA repair disorder (PARD). PARD symptoms range from UV sensitivity, neurodegeneration, telangiectasia, and premature aging. We, and others, previously showed that the S228I variant changes the protein-binding pocket of PCNA to a conformation that impairs interactions with specific partners. Here, we report a second PCNA substitution (C148S) that also causes PARD. Unlike PCNA-S228I, PCNA-C148S has WT-like structure and affinity toward partners. In contrast, both disease-associated variants possess a thermostability defect. Furthermore, patient-derived cells homozygous for the C148S allele exhibit low levels of chromatin-bound PCNA and display temperature-dependent phenotypes. The stability defect of both PARD variants indicates that PCNA levels are likely an important driver of PARD disease. These results significantly advance our understanding of PARD and will likely stimulate additional work focused on clinical, diagnostic, and therapeutic aspects of this severe disease.
ISSN:0021-9258
1083-351X
DOI:10.1016/j.jbc.2023.104656