Structural basis for coupled DNA replication and uracil repair by a family of DNA polymerases from phages with T-modified genomes
Abstract
Replicative DNA polymerases (DNAPs) play a critical role in genome duplication, ensuring the accurate transmission of genetic information in all domains of life. DNAPs are also essential for DNA viruses, as well as bacteriophages, where a uracil-DNA glycosylase (UDG) is often encoded in trans or is present in the DNAP gene. Here, we identify a new group of A-family DNAPs in phages that are fused to an active UDG domain and contain other large insertions. Several members of this subfamily, including phages SP-15 and YerA41, are known to be hypermodified on their thymidine base through glycosylation of a linker attached to the C5 position of thymine. We determined the atomic cryo-EM structures for two of its members in various active functional and conformational states, from YerA41 and phiLo phages. The structures reveal how these large DNAPs function as replicative DNAPs, and how they can recognize dU bases ahead of the replication fork through their UDG domain, generating abasic sites that are preferentially bypassed through dA incorporation. Such dU errors would need to be eliminated to preserve phage genome integrity. Additionally, we report the co-occurrence of both an X-family DNAP and a DNA ligase in the corresponding phage genomes and show that both enzymes can execute the final steps of base excision repair most probably on-the-fly during replication, revealing a DNA-replication-coupled repair process. The structures of these large polymerases can serve as a model of other large platform DNAPs that can recruit additional enzymatic activities necessary for phage or virus survival.
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BibTeX
@article{missoury2026structural,
title = {{Structural basis for coupled DNA replication and uracil repair by a family of DNA polymerases from phages with T-modified genomes}},
author = {Sophia Missoury and Soizick Lucas-Staat and Rémi Sieskind and Marc Delarue},
journal = {Nucleic Acids Research},
year = {2026},
month = oct,
doi = {10.1093/nar/gkag1018},
url = {https://pasteur.hal.science/pasteur-05844437v1},
note = {CC BY-NC 4.0},
}
RIS
TY - JOUR
TI - Structural basis for coupled DNA replication and uracil repair by a family of DNA polymerases from phages with T-modified genomes
AU - Sophia Missoury
AU - Soizick Lucas-Staat
AU - Rémi Sieskind
AU - Marc Delarue
PY - 2026
DA - 2026/10/01
JO - Nucleic Acids Research
DO - 10.1093/nar/gkag1018
UR - https://pasteur.hal.science/pasteur-05844437v1
AB - Replicative DNA polymerases (DNAPs) play a critical role in genome duplication, ensuring the accurate transmission of genetic information in all domains of life. DNAPs are also essential for DNA viruses, as well as bacteriophages, where a uracil-DNA glycosylase (UDG) is often encoded in trans or is present in the DNAP gene. Here, we identify a new group of A-family DNAPs in phages that are fused to an active UDG domain and contain other large insertions. Several members of this subfamily, including phages SP-15 and YerA41, are known to be hypermodified on their thymidine base through glycosylation of a linker attached to the C5 position of thymine. We determined the atomic cryo-EM structures for two of its members in various active functional and conformational states, from YerA41 and phiLo phages. The structures reveal how these large DNAPs function as replicative DNAPs, and how they can recognize dU bases ahead of the replication fork through their UDG domain, generating abasic sites that are preferentially bypassed through dA incorporation. Such dU errors would need to be eliminated to preserve phage genome integrity. Additionally, we report the co-occurrence of both an X-family DNAP and a DNA ligase in the corresponding phage genomes and show that both enzymes can execute the final steps of base excision repair most probably on-the-fly during replication, revealing a DNA-replication-coupled repair process. The structures of these large polymerases can serve as a model of other large platform DNAPs that can recruit additional enzymatic activities necessary for phage or virus survival.
SN - 0305-1048
SN - 1362-4962
ER -