DCTPP1 orchestrates dCTP pool dynamics and mtDNA stability in quiescent cells
Belén Fernández1, Guiomar Pérez-Moreno2, Blanca Martínez-Arribas2
1Instituto de Parasitología y Biomedicina "López-Neyra" (IPBLN), CSIC, Parque Tecnológico de Ciencias de la Salud. Avda. del Conocimiento, Granada, Spain. belenfernandez@ipb.csic.es.
Cell Death & Disease
|March 27, 2026
Summary
Human all-α dCTP pyrophosphatase 1 (DCTPP1) enzyme is crucial for maintaining deoxynucleotide triphosphate (dNTP) balance, particularly in mitochondria. Lowering DCTPP1 levels can restore mitochondrial DNA (mtDNA) stability in disease models.
Area of Science:
- Biochemistry
- Molecular Biology
- Genetics
Background:
- Defects in nucleotide metabolism and deoxynucleotide triphosphate (dNTP) pool imbalances are linked to human diseases like cancer and mitochondrial disorders.
- Sustaining mitochondrial DNA (mtDNA) replication and repair requires a continuous nucleotide supply, even in non-replicating cells.
- Human all-α dCTP pyrophosphatase 1 (DCTPP1) is a hydrolase critical for nucleotide homeostasis, but its role in mtDNA stability is unknown.
Purpose of the Study:
- To investigate the role of DCTPP1 in maintaining nucleotide homeostasis and mtDNA stability in quiescent cells.
- To analyze the impact of DCTPP1 depletion on pyrimidine metabolism and dNTP pools.
- To explore the therapeutic potential of targeting DCTPP1 in mitochondrial disorders like mitochondrial neurogastrointestinal encephalomyopathy (MNGIE).
Main Methods:
- Detailed analysis of pyrimidine metabolism enzymes in quiescent (non-dividing) cells.
- Assessment of DCTPP1 localization within cells.
- Experimental manipulation of DCTPP1 levels (depletion/knockdown) and observation of effects on dNTP pools and mtDNA.
- Utilizing an in vitro MNGIE model involving thymidine overloading.
Main Results:
- DCTPP1 was found to localize predominantly in mitochondria during quiescence.
- DCTPP1 depletion led to increased de novo thymidylate synthesis and expanded dCTP and dGTP pools.
- In a model of MNGIE, thymidine overload caused dCTP depletion and mtDNA loss, which were reversed by DCTPP1 knockdown, restoring dCTP levels and increasing mtDNA copy number.
Conclusions:
- DCTPP1 plays a critical role in regulating mitochondrial dNTP pools and maintaining mtDNA stability.
- Down-regulation of DCTPP1 may be a compensatory mechanism in diseases with secondary dCTP depletion.
- DCTPP1 represents a potential therapeutic target for mitochondrial DNA depletion syndromes such as MNGIE.
Related Concept Videos
02:36DNA Damage can Stall the Cell Cycle
10.4K
In response to DNA damage, cells can pause the cell cycle to assess and repair the breaks. However, the cell must check the DNA at certain critical stages during the cell cycle. If the cell cycle pauses before DNA replication, the cells will contain twice the amount of DNA. On the other hand, if cells arrest after DNA replication but before mitosis, they will contain four times the normal amount of DNA. With a host of specialized proteins at their disposal,cells must use the right protein at...
10.4K
02:36DNA Damage Can Stall the Cell Cycle
3.4K
In response to DNA damage, cells can pause the cell cycle to assess and repair the breaks. However, the cell must check the DNA at certain critical stages during the cell cycle. If the cell cycle pauses before DNA replication, the cells will contain twice the amount of DNA. On the other hand, if cells arrest after DNA replication but before mitosis, they will contain four times the normal amount of DNA. With a host of specialized proteins at their disposal,cells must use the right protein at...
3.4K
02:37Restarting Stalled Replication Forks
6.5K
DNA replication is initiated at sites containing predefined DNA sequences known as origins of replication. DNA is unwound at these sites by the minichromosome maintenance (MCM) helicase and other factors such as Cdc45 and the associated GINS complex.The unwound single strands are protected by replication protein A (RPA) until DNA polymerase starts synthesizing DNA at the 5’ end of the strand in the same direction as the replication fork. To prevent the replication fork from falling apart,...
6.5K
02:17Microtubule Instability
6.4K
Microtubules are hollow cylindrical filaments having a diameter of approximately 25 nm and a length that varies from 200 nm to 25 μm. GTP-bound tubulin subunits form αβ-heterodimers for microtubule assembly. These core building blocks interact longitudinally, polymerizing into protofilaments. The protofilaments then interact with one another through lateral bonding forces to form stable cylindrical microtubules. These cylindrical filaments are dynamic as they undergo repeated...
6.4K
02:15M-Cdk Drives Transition Into Mitosis
6.8K
Checkpoints throughout the cell cycle serve as safeguards and gatekeepers, allowing the cell cycle to progress in favorable conditions and slow or halt it in problematic ones. This regulation is known as the cell cycle control system.
Cyclin-dependent kinases, or Cdks, work in concert with cyclins to control cell cycle transitions. M-Cdk, a complex of Cdk1 bound to M cyclin, is a well-known example of this coordinated control that drives the transition from the G2 to the M phase.
M cyclin...
Cyclin-dependent kinases, or Cdks, work in concert with cyclins to control cell cycle transitions. M-Cdk, a complex of Cdk1 bound to M cyclin, is a well-known example of this coordinated control that drives the transition from the G2 to the M phase.
M cyclin...
6.8K
01:45Mitochondrial Membranes
17.8K
A single mitochondrion is a bean-shaped organelle enclosed by a double-membrane system. The outer membrane of mitochondria is smooth and contains many porins - the integral membrane transporters. Porins enable free diffusion of ions and small uncharged molecules through the outer mitochondrial membrane but limit the transport of molecules larger than 5000 Daltons. Further, the outer mitochondrial membrane forms a unique structure called membrane contact sites with other subcellular organelles,...
17.8K