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

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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 ; Leao, Emilia K. E. ; Kok, Fernand ; Menck, Carlos F. M. ; Jorge, Alexander A. L. ; Kelch, Brian A.

• Document type: Journal article
• Source: Journal of Biological Chemistry; v. 299, n. 5, p. 16-pg., 2023-04-26.

Abstract

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) substitu-tion in PCNA was described to underlie a rare DNA repair dis-order 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. (AU)

• FAPESP's process: 18/10893-6 - Prospective evaluation of exome sequencing in the etiological investigation of syndromic short stature patients without clinical diagnosis
• Grantee: Bruna Lucheze Freire
• Support Opportunities: Scholarships in Brazil - Doctorate
• FAPESP's process: 13/03236-5 - New approaches and methodologies in molecular-genetic studies of growth and pubertal development disorders
• Grantee: Alexander Augusto de Lima Jorge
• Support Opportunities: Research Projects - Thematic Grants