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Published on: April 4, 2018
Structural and functional impact of the POLD1 Ser605del variant in MDPL syndrome: insights from protein-protein
Michela Murdocca1, Isabella Romeo2,3, Serena Maccaroni1
1Department of Biomedicine and Prevention, University of Rome Tor Vergata, Via Montpellier 1, Rome, 00133, Italy.
Background:
Mandibular hypoplasia, Deafness, Progeroid features, and Lipodystrophy (MDPL) syndrome is a very rare genetic disorder linked to variants in the POLD1 gene, which encodes the catalytic subunit of DNA polymerase delta, a key enzyme involved in DNA replication and repair. Most patients carry a recurrent in frame deletion (p.Ser605del) within the active site of the p125 subunit. Despite its rarity, understanding the functional consequences of the Ser605del variant has broad implications for aging-related diseases and genome stability.
Methods:
We combined structural modelling, molecular dynamics simulations, and protein-protein interaction (PPIs) analyses to evaluate the impact of Ser605del in the catalytic activity of DNA polymerase delta. Bioinformatic tools were applied to characterize its interaction network. RT-q PCR and Western Blot were performed to assess expression levels of POLD1, TRF1, and PARP1 in human dermal fibroblasts (HDFs) of three MDPL patients of different ages. Cells were monitored at different passages, both in basal condition and after damage by X irradiation. POLD1/TRF1 interaction was confirmed by immunoprecipitation analyses.
Results:
Using molecular docking, molecular dynamics simulations and thermodynamic analyses, we found that Ser605del affects the DNA-binding site, impairing dTTP binding. The deletion alters short linear motifs involved in protein-protein interactions (PPIs), allowing the acquisition of a F/Y-X-L-X-P (FSLYP) consensus sequence with TRF1, a telomeric protein. In silico analyses highlighted a stronger interaction between the Ser605del POLD1 variant and TRF1. Experiments on MDPL fibroblasts confirmed a stronger POLD1-TRF1 binding and revealed dysregulation of PARP1, involved in telomere maintenance. Following X-ray irradiation, aimed at exacerbating the cellular phenotype, we observed a decreasing trend in these markers, which reached statistical significance particularly in one older patient.
Conclusions:
We identified a novel short linear motif (FSLYP) in the Ser605del POLD1 protein that mediates abnormal interaction with TRF1, revealing a structural and functional link between POLD1 and telomere biology, contributing to premature aging phenotypes. This work provides new insights into MDPL pathogenesis and lays the foundation for future research into aging-related therapies.
Insights
The POLD1 Ser605del variant in Mandibular hypoplasia, Deafness, Progeroid features, and Lipodystrophy (MDPL) syndrome disrupts DNA polymerase delta function and links to telomere biology, contributing to premature aging.
Area of Science:
- Molecular Biology
- Genetics
- Biochemistry
Background:
- Mandibular hypoplasia, Deafness, Progeroid features, and Lipodystrophy (MDPL) syndrome is a rare genetic disorder caused by POLD1 gene variants.
- A common variant, POLD1 Ser605del, affects DNA polymerase delta, crucial for DNA replication and repair, with implications for aging and genome stability.
Purpose of the Study:
- To investigate the functional consequences of the POLD1 Ser605del variant on DNA polymerase delta activity and protein interactions.
- To explore the link between POLD1 dysfunction, telomere biology, and the premature aging phenotypes observed in MDPL syndrome.
Main Methods:
- Combined structural modeling, molecular dynamics simulations, and protein-protein interaction (PPI) analyses to assess the impact of Ser605del.
- Bioinformatic tools were used to characterize the interaction network of the variant.
- Expression levels of POLD1, TRF1, and PARP1 were analyzed in MDPL patient fibroblasts using RT-qPCR and Western Blot, with and without X-ray irradiation.
Main Results:
- The Ser605del variant impairs DNA binding and dTTP binding in DNA polymerase delta.
- This deletion creates a novel FSLYP motif, enhancing interaction with the telomeric protein TRF1, and dysregulating PARP1 involved in telomere maintenance.
- Experiments confirmed increased POLD1-TRF1 binding and PARP1 dysregulation in MDPL fibroblasts, with a decreasing trend observed after irradiation, particularly in older patients.
Conclusions:
- A novel FSLYP motif in Ser605del POLD1 mediates aberrant TRF1 interaction, establishing a link between POLD1, telomere biology, and premature aging.
- This study provides new insights into MDPL pathogenesis and suggests potential therapeutic avenues targeting aging-related pathways.
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