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PAXX and its paralogs synergistically direct DNA polymerase λ activity in DNA repair

Author

Listed:
  • Andrew Craxton

    (MRC Toxicology Unit)

  • Deeksha Munnur

    (MRC Toxicology Unit
    Sir William Dunn School of Pathology, South Parks Road, University of Oxford)

  • Rebekah Jukes-Jones

    (MRC Toxicology Unit)

  • George Skalka

    (MRC Toxicology Unit)

  • Claudia Langlais

    (MRC Toxicology Unit)

  • Kelvin Cain

    (MRC Toxicology Unit)

  • Michal Malewicz

    (MRC Toxicology Unit)

Abstract

PAXX is a recently identified component of the nonhomologous end joining (NHEJ) DNA repair pathway. The molecular mechanisms of PAXX action remain largely unclear. Here we characterise the interactomes of PAXX and its paralogs, XLF and XRCC4, to show that these factors share the ability to interact with DNA polymerase λ (Pol λ), stimulate its activity and are required for recruitment of Pol λ to laser-induced DNA damage sites. Stimulation of Pol λ activity by XRCC4 paralogs requires a direct interaction between the SP/8 kDa domain of Pol λ and their N-terminal head domains to facilitate recognition of the 5′ end of substrate gaps. Furthermore, PAXX and XLF collaborate with Pol λ to promote joining of incompatible DNA ends and are redundant in supporting Pol λ function in vivo. Our findings identify Pol λ as a novel downstream effector of PAXX function and show XRCC4 paralogs act in synergy to regulate polymerase activity in NHEJ.

Suggested Citation

  • Andrew Craxton & Deeksha Munnur & Rebekah Jukes-Jones & George Skalka & Claudia Langlais & Kelvin Cain & Michal Malewicz, 2018. "PAXX and its paralogs synergistically direct DNA polymerase λ activity in DNA repair," Nature Communications, Nature, vol. 9(1), pages 1-16, December.
    • Handle: RePEc:nat:natcom:v:9:y:2018:i:1:d:10.1038_s41467-018-06127-y
    DOI: 10.1038/s41467-018-06127-y
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    Cited by:

    1. Xabier Vergara & Anna G. Manjón & Marcel Haas & Ben Morris & Ruben Schep & Christ Leemans & Anoek Friskes & Roderick L. Beijersbergen & Mathijs A. Sanders & René H. Medema & Bas Steensel, 2024. "Widespread chromatin context-dependencies of DNA double-strand break repair proteins," Nature Communications, Nature, vol. 15(1), pages 1-14, December.
    2. Aldo S. Bader & Martin Bushell, 2023. "iMUT-seq: high-resolution DSB-induced mutation profiling reveals prevalent homologous-recombination dependent mutagenesis," Nature Communications, Nature, vol. 14(1), pages 1-16, December.

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