Recent Projects
The function of PrimPol in mtDNA maintenance
Failure to maintain mtDNA integrity can lead to a wide variety of neuromuscular disorders. We have previously shown that PrimPol is specifically required for replication reinitiation after mtDNA damage. PrimPol synthesizes DNA primers, which can be elongated by the mitochondrial replicative polymerase γ, a solution to reprime replication beyond DNA lesions and to prevent loss of mtDNA integrity. Our on-going studies will address the mechanisms by which PrimPol is regulated to protect the mitochondrial genome from intrinsic and extrinsic stressors on a molecular but also on a cellular level.
Function of G-quadruplex DNA in mtDNA instability and gene expression
G-quaduplexes (G4s) are four-stranded secondary DNA structures that play important roles in regulating gene expression, but are also associated with genome instability. Many endogenous DNA G4s have been investigated and mapped in the nuclear genome, but functional studies on potential G4-forming sequences in the mitochondrial genome are limited. With our research we aim to specifically modulate and visualize mitochondrial G4 structures to understand how they contribute to mtDNA instability.
Mechanism of mtDNA deletion formation in disease
Mitochondrial DNA deletion formation is a relevant question not only to understand the early development and progression of a large number of mitochondrial disorders, but also for other, more common conditions that involve mtDNA deletion accumulation such as Parkinson’s disease. In our laboratory we aim to elucidate the mechanism by which these mtDNA deletions accumulate.
Consequence and cellular function of single embedded ribonucleotides in mtDNA
Ribonucleotides are frequently incorporated in both the nuclear and mitochondrial DNA during normal replication processes due to their abundance and chemical similarity to deoxynucleotides (dNTPs). Ribonucleotides inserted into DNA (rNMPs) change the chemical and structural properties of the DNA. Consequently, rNMPs that persist in nuclear DNA can lead to severe replication stress. In contrast, mitochondrial gene expression seems tolerant to the presence of rNMPs in the mtDNA template. We aim to understand how the rNMP tolerance of the mtDNA is achieved but are also intrigued with the possibility that single ribonucleotides embedded in the mtDNA have a cellular function.