Investigating the Role of Replication Restart in Preventing Pathogenic Mitochondrial DNA Deletions

Human mitochondria are essential for energy production, and critical components are encoded in mitochondrial DNA (mtDNA).

Accordingly, deletions in mtDNA can lead to energy defects and disease: mtDNA deletions do not only causes rare mitochondrial disorders but is also observed in the affected tissues of Parkinson´s disease patients.However, the cellular mechanisms that protect against mtDNA deletion accumulation remain unclear, hampering thetreatment of mtDNA deletion-related disease.

MtDNA deletions are shown to result from disturbances that stall the mtDNA replication fork.

We recently discovered that PrimPol, a primase-polymerase enzyme, resolves stalled mtDNA replication by re-initiating DNA synthesis. This new pathway of re-initiation is a top candidate for protecting us from mtDNA deletion formation. However, the molecular mechanisms of PrimPol-dependent re-initiation remain unclear.

This project will investigate PrimPol-dependent mtDNA replication re-start and its role in mtDNA maintenance, focusing on: (1) the role of the accessory factor PolDIP2, (2) elucidation of the complete machinery, and (3) corroborating the protective role of the pathway against mtDNA deletion formation.

Understanding this mechanism is vital for guiding future research to prevent or alleviate mtDNA deletions in various diseases.

The research will be conducted by a PhD student and a postdoctoral researcher using a combination of in vitro protein biochemistry and human cell-based approaches.