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Peer-reviewedCC BYNature communications

End processing in NHEJ by Polymerase λ and PNKP is coordinated during short-range synapsis.

  • Alex Vogt1,2
  • Andrea M Kaminski3
  • Jason G Williams4
  • Tasmin Naila5,6,7
  • Danny Laurent8
  • Alan E Tomkinson5,6,7
  • Susan P Lees-Miller8
  • Lars C Pedersen3
  • Thomas A Kunkel3
  • Yuan He9,10
10 affiliations
  1. 1Department of Molecular Biosciences, Northwestern University, Evanston, IL, USA.
  2. 2Interdisciplinary Biological Sciences Program, Northwestern University, Evanston, IL, USA.
  3. 3Genome Integrity and Structural Biology Laboratory, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, Durham, NC, USA.
  4. 4Epigenetics and RNA Biology Laboratory, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, Durham, NC, USA.
  5. 5Department of Internal Medicine, University of New Mexico, Albuquerque, NM, USA.
  6. 6Department of Molecular Genetics & Microbiology, University of New Mexico, Albuquerque, NM, USA.
  7. 7University of New Mexico Comprehensive Cancer Center, University of New Mexico, Albuquerque, NM, USA.
  8. 8Department of Biochemistry and Molecular Biology and Robson DNA Science Centre, Arnie Charbonneau Cancer Institute, University of Calgary, Calgary, AB, Canada.
  9. 9Department of Biophysics, Johns Hopkins University, Baltimore, MD, USA. [email protected].
  10. 10Department of Biology, Johns Hopkins University, Baltimore, MD, USA. [email protected].
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Abstract

Non-homologous end joining (NHEJ) is a major pathway of DNA double strand break (DSB) repair, capable of directly joining both damaged strands of DNA through the coordinated activities of repair factors that detect the termini, physically bridge them together, and perform the chemistry necessary to complete repair. NHEJ is capable of repairing a variety of damaged DNA, employing various accessory end-processing factors to resolve chemically blocked ends, trim overhangs, and fill gaps in order to achieve directly ligatable DNA ends. To investigate the molecular mechanisms underlying end-processing, we determine the cryo-EM structure of the NHEJ specific polymerase Pol λ bound to the short-range synaptic complex, detailing the mode of its recruitment to the complex as well as a putative model for its activity. Furthermore, the coordinated end-processing activities of the short-range (SR) synaptic complex simultaneously bound by both Pol λ and PNKP, another accessory factor, demonstrates the ability of NHEJ to form large, multifunctional repair complexes capable of processing a variety of different DNA end structures to effect repair.

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Cite

BibTeXRIS
BibTeX
@article{vogt2026processing,
  title = {{End processing in NHEJ by Polymerase λ and PNKP is coordinated during short-range synapsis.}},
  author = {Alex Vogt and Andrea M Kaminski and Jason G Williams and Tasmin Naila and Danny Laurent and Alan E Tomkinson and Susan P Lees-Miller and Lars C Pedersen and Thomas A Kunkel and Yuan He},
  journal = {Nature communications},
  year = {2026},
  month = sep,
  doi = {10.1038/s41467-026-77503-2},
  url = {https://europepmc.org/article/MED/42850230},
  note = {CC BY},
}
RIS
TY  - JOUR
TI  - End processing in NHEJ by Polymerase λ and PNKP is coordinated during short-range synapsis.
AU  - Alex Vogt
AU  - Andrea M Kaminski
AU  - Jason G Williams
AU  - Tasmin Naila
AU  - Danny Laurent
AU  - Alan E Tomkinson
AU  - Susan P Lees-Miller
AU  - Lars C Pedersen
AU  - Thomas A Kunkel
AU  - Yuan He
PY  - 2026
DA  - 2026/09/09
JO  - Nature communications
DO  - 10.1038/s41467-026-77503-2
UR  - https://europepmc.org/article/MED/42850230
AB  - Non-homologous end joining (NHEJ) is a major pathway of DNA double strand break (DSB) repair, capable of directly joining both damaged strands of DNA through the coordinated activities of repair factors that detect the termini, physically bridge them together, and perform the chemistry necessary to complete repair. NHEJ is capable of repairing a variety of damaged DNA, employing various accessory end-processing factors to resolve chemically blocked ends, trim overhangs, and fill gaps in order to achieve directly ligatable DNA ends. To investigate the molecular mechanisms underlying end-processing, we determine the cryo-EM structure of the NHEJ specific polymerase Pol λ bound to the short-range synaptic complex, detailing the mode of its recruitment to the complex as well as a putative model for its activity. Furthermore, the coordinated end-processing activities of the short-range (SR) synaptic complex simultaneously bound by both Pol λ and PNKP, another accessory factor, demonstrates the ability of NHEJ to form large, multifunctional repair complexes capable of processing a variety of different DNA end structures to effect repair.
SN  - 2041-1723
ER  -