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Interpreting the effects of DNA polymerase variants at the structural level

Arnaudi, Matteo ; Krzesińska, Karolina ; Beltrame, Ludovica ; Besora, Pablo Sánchez Izquierdo ; Tiberti, Matteo ; Nilbert, Mef LU ; Rohlin, Anna LU and Papaleo, Elena (2026) In Molecular Oncology 20(8). p.2054-2084
Abstract

Genetic variants in the DNA polymerase enzymes POLE and POLD1 can affect protein function by altering stability, catalysis, DNA binding, and interactions with other biomolecules. Understanding the structural basis of these variants is important for a comprehensive interpretation of variant impact. In this study, we used MAVISp, a modular structure-based framework, and molecular dynamics simulations to analyze over 60 000 missense variants of POLE and POLD1. By integrating results from changes in folding and binding free energies, local alterations in the proximity of the active or phosphorylation sites, we provided a detailed structural interpretation of variants reported across various databases, including ClinVar, COSMIC, and... (More)

Genetic variants in the DNA polymerase enzymes POLE and POLD1 can affect protein function by altering stability, catalysis, DNA binding, and interactions with other biomolecules. Understanding the structural basis of these variants is important for a comprehensive interpretation of variant impact. In this study, we used MAVISp, a modular structure-based framework, and molecular dynamics simulations to analyze over 60 000 missense variants of POLE and POLD1. By integrating results from changes in folding and binding free energies, local alterations in the proximity of the active or phosphorylation sites, we provided a detailed structural interpretation of variants reported across various databases, including ClinVar, COSMIC, and cBioPortal. Moreover, we predicted the functional consequences of variants not found yet in disease-related databases, thereby creating a comprehensive catalog for future studies. Of note, our approach enabled us to classify 364 Variants of Uncertain Significance (VUS) as PP3 evidence and 323 as BP4 evidence, in accordance with the American College of Medical Genetics and Genomics (ACMG) guidelines. Additionally, we identified a group of variants that could alter the native orientation of the residues within the catalytic site of the exonuclease domain, such as POLE variants P297S and P436R. Finally, we identified a group of variants predicted to affect DNA-binding affinity and rationalized their effects in terms of different energetic contributions and structural features. Collectively, our results not only advance our understanding of protein variant effects in POLE and POLD1 at the structural level but also support future studies aimed at variant classification, variant prioritization for experimental studies, and functional interpretation across diverse biological contexts.

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author
; ; ; ; ; ; and
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
cancer genomics, free energy calculations, long-range structural communication, protein stability, protein structures, variant effects
in
Molecular Oncology
volume
20
issue
8
pages
31 pages
publisher
John Wiley & Sons Inc.
external identifiers
  • pmid:42204826
  • scopus:105040345223
ISSN
1574-7891
DOI
10.1002/1878-0261.70255
language
English
LU publication?
yes
id
dcf83d9c-28e0-432d-a294-9975b9073069
date added to LUP
2026-09-22 15:14:34
date last changed
2026-09-23 03:00:03
@article{dcf83d9c-28e0-432d-a294-9975b9073069,
  abstract     = {{<p>Genetic variants in the DNA polymerase enzymes POLE and POLD1 can affect protein function by altering stability, catalysis, DNA binding, and interactions with other biomolecules. Understanding the structural basis of these variants is important for a comprehensive interpretation of variant impact. In this study, we used MAVISp, a modular structure-based framework, and molecular dynamics simulations to analyze over 60 000 missense variants of POLE and POLD1. By integrating results from changes in folding and binding free energies, local alterations in the proximity of the active or phosphorylation sites, we provided a detailed structural interpretation of variants reported across various databases, including ClinVar, COSMIC, and cBioPortal. Moreover, we predicted the functional consequences of variants not found yet in disease-related databases, thereby creating a comprehensive catalog for future studies. Of note, our approach enabled us to classify 364 Variants of Uncertain Significance (VUS) as PP3 evidence and 323 as BP4 evidence, in accordance with the American College of Medical Genetics and Genomics (ACMG) guidelines. Additionally, we identified a group of variants that could alter the native orientation of the residues within the catalytic site of the exonuclease domain, such as POLE variants P297S and P436R. Finally, we identified a group of variants predicted to affect DNA-binding affinity and rationalized their effects in terms of different energetic contributions and structural features. Collectively, our results not only advance our understanding of protein variant effects in POLE and POLD1 at the structural level but also support future studies aimed at variant classification, variant prioritization for experimental studies, and functional interpretation across diverse biological contexts.</p>}},
  author       = {{Arnaudi, Matteo and Krzesińska, Karolina and Beltrame, Ludovica and Besora, Pablo Sánchez Izquierdo and Tiberti, Matteo and Nilbert, Mef and Rohlin, Anna and Papaleo, Elena}},
  issn         = {{1574-7891}},
  keywords     = {{cancer genomics; free energy calculations; long-range structural communication; protein stability; protein structures; variant effects}},
  language     = {{eng}},
  number       = {{8}},
  pages        = {{2054--2084}},
  publisher    = {{John Wiley & Sons Inc.}},
  series       = {{Molecular Oncology}},
  title        = {{Interpreting the effects of DNA polymerase variants at the structural level}},
  url          = {{http://dx.doi.org/10.1002/1878-0261.70255}},
  doi          = {{10.1002/1878-0261.70255}},
  volume       = {{20}},
  year         = {{2026}},
}