The POLγ Y951N patient mutation disrupts the switch between DNA synthesis and proofreading, triggering mitochondrial DNA instability

• 成果类型: Article
• 署名作者: Forslund, Josefin M. E.; Nguyen, Tran V. H.; Parkash, Vimal; Berner, Andreas; Goffart, Steffi; Wanrooij, Paulina H.; Johansson, Erik; Wanrooij, Sjoerd
• 署名单位: Umea University; University of Eastern Finland
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-15035
• DOI: 10.1073/pnas.2417477122
• 发表日期: 2025-04-22
• 关键词: polymerase-gamma; autosomal-dominant; exonuclease domain; replication; roles

摘要

Mitochondrial DNA (mtDNA) stability, essential for cellular energy production, relies on DNA polymerase gamma (POL gamma). Here, we show that the POL gamma Y951N disease-causing mutation induces replication stalling and severe mtDNA depletion. However, unlike other POL gamma disease-causing mutations, Y951N does not directly impair exonuclease activity and only mildly affects polymerase activity. Instead, we found that Y951N compromises the enzyme's ability to efficiently toggle between DNA synthesis and degradation, and is thus a patient-derived mutation with impaired polymerase-exonuclease switching. These findings provide insights into the intramolecular switch when POL gamma proofreads the newly synthesized DNA strand and reveal a new mechanism for causing mitochondrial DNA instability.