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Structural basis of gap-filling DNA synthesis in the nucleosome by DNA Polymerase β

Author

Listed:
  • Tyler M. Weaver

    (University of Kansas Medical Center
    University of Kansas Medical Center)

  • Benjamin J. Ryan

    (University of Kansas Medical Center)

  • Spencer H. Thompson

    (University of Kansas Medical Center)

  • Adil S. Hussen

    (University of Kansas Medical Center)

  • Jonah J. Spencer

    (University of Kansas Medical Center)

  • Zhen Xu

    (University of Iowa Carver College of Medicine)

  • Nicholas J. Schnicker

    (University of Iowa Carver College of Medicine
    University of Iowa Carver College of Medicine)

  • Bret D. Freudenthal

    (University of Kansas Medical Center
    University of Kansas Medical Center
    University of Kansas Cancer Center)

Abstract

Single-strand breaks (SSBs) are one of the most prevalent forms of DNA damage found in the chromatinized genome and are repaired by single-strand break repair (SSBR) or base excision repair (BER). DNA polymerase beta (Pol β) is the primary enzyme responsible for processing the 1-nt gap intermediate in chromatin during SSBR and BER. To date, the mechanism used by Pol β to process a 1-nt gap in the context of chromatin remains poorly understood. Here, we use biochemical assays and cryogenic electron microscopy (cryo-EM) to determine the kinetic and structural basis of gap-filling DNA synthesis in the nucleosome by Pol β. This work establishes that Pol β uses a global DNA sculpting mechanism for processing 1-nt gaps in the nucleosome during SSBR and BER, providing fundamental insight into DNA repair in chromatin.

Suggested Citation

  • Tyler M. Weaver & Benjamin J. Ryan & Spencer H. Thompson & Adil S. Hussen & Jonah J. Spencer & Zhen Xu & Nicholas J. Schnicker & Bret D. Freudenthal, 2025. "Structural basis of gap-filling DNA synthesis in the nucleosome by DNA Polymerase β," Nature Communications, Nature, vol. 16(1), pages 1-15, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-57915-2
    DOI: 10.1038/s41467-025-57915-2
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    References listed on IDEAS

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    1. Huifen Cao & Lorena Salazar-García & Fan Gao & Thor Wahlestedt & Chun-Lin Wu & Xueer Han & Ye Cai & Dongyang Xu & Fang Wang & Lu Tang & Natalie Ricciardi & DingDing Cai & Huifang Wang & Mario P. S. Ch, 2019. "Novel approach reveals genomic landscapes of single-strand DNA breaks with nucleotide resolution in human cells," Nature Communications, Nature, vol. 10(1), pages 1-14, December.
    2. Gabrielle J. Grundy & Luis M. Polo & Zhihong Zeng & Stuart L. Rulten & Nicolas C. Hoch & Pathompong Paomephan & Yingqi Xu & Steve M. Sweet & Alan W. Thorne & Antony W. Oliver & Steve J. Matthews & Lau, 2016. "PARP3 is a sensor of nicked nucleosomes and monoribosylates histone H2BGlu2," Nature Communications, Nature, vol. 7(1), pages 1-12, November.
    3. Natasha Ramakrishnan & Tyler M. Weaver & Lindsey N. Aubuchon & Ayda Woldegerima & Taylor Just & Kevin Song & Alessandro Vindigni & Bret D. Freudenthal & Priyanka Verma, 2024. "Nucleolytic processing of abasic sites underlies PARP inhibitor hypersensitivity in ALC1-deficient BRCA mutant cancer cells," Nature Communications, Nature, vol. 15(1), pages 1-17, December.
    4. Mengtian Ren & Fabian Gut & Yilan Fan & Jingke Ma & Xiajing Shan & Aysenur Yikilmazsoy & Mariia Likhodeeva & Karl-Peter Hopfner & Chuanzheng Zhou, 2024. "Structural basis for human OGG1 processing 8-oxodGuo within nucleosome core particles," Nature Communications, Nature, vol. 15(1), pages 1-11, December.
    5. George E. Ronson & Ann Liza Piberger & Martin R. Higgs & Anna L. Olsen & Grant S. Stewart & Peter J. McHugh & Eva Petermann & Nicholas D. Lakin, 2018. "PARP1 and PARP2 stabilise replication forks at base excision repair intermediates through Fbh1-dependent Rad51 regulation," Nature Communications, Nature, vol. 9(1), pages 1-12, December.
    6. Tyler M. Weaver & Nicole M. Hoitsma & Jonah J. Spencer & Lokesh Gakhar & Nicholas J. Schnicker & Bret D. Freudenthal, 2022. "Structural basis for APE1 processing DNA damage in the nucleosome," Nature Communications, Nature, vol. 13(1), pages 1-12, December.
    7. Karolin Luger & Armin W. Mäder & Robin K. Richmond & David F. Sargent & Timothy J. Richmond, 1997. "Crystal structure of the nucleosome core particle at 2.8 Å resolution," Nature, Nature, vol. 389(6648), pages 251-260, September.
    8. Cameron Cordero & Kavi P. M. Mehta & Tyler M. Weaver & Justin A. Ling & Bret D. Freudenthal & David Cortez & Steven A. Roberts, 2024. "Contributing factors to the oxidation-induced mutational landscape in human cells," Nature Communications, Nature, vol. 15(1), pages 1-18, December.
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