The POLγ Y951N patient mutation disrupts the switch between DNA synthesis and proofreading, triggering mitochondrial DNA instability
Year: 2025
Type: article
Abstract: Mitochondrial DNA (mtDNA) stability, essential for cellular energy production, relies on DNA polymerase gamma (POLγ). Here, we show that the POLγ Y951N disease-causing mutation induces replication stalling and severe mtDNA depletion. However, unlike other POLγ 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 POLγ proofreads the newly synthesized DNA strand and reveal a new mechanism for causing mitochondrial DNA instability.
Institutions: Umeå University, University of Eastern Finland
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: hybrid
Awards: G109558250, G1771155026, G1824882415, Fidelity of DNA replication – cancer associated substitutions in DNA polymerase epsilon, G1869643909, G3301101743, G3518649275, G4066480865, Investigating the Role of Replication Restart in Preventing Pathogenic Mitochondrial DNA Deletions, G599142747, G6265702644, G712881263, G7185425644
OpenAlex ID: W4409499780