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A CDK1 phospho-switch reprograms TRAIP to unload replisomes in mitosis

  • Geylani Can1,2,3
  • Maksym Shyian1
  • Archana Krishnamoorthy2,3
  • Samreen Ahmed4,5
  • Yang Lim1,6
  • Alex Wu7,1
  • Raphael Pavani8
  • Manal S. Zaher1,9
  • André Nussenzweig8
  • Markus Räschle10
  • Thomas E. Wilson4,5
  • Thomas W. Glover4,5
2 more authors
  • Johannes C. Walter1,11
  • David S. Pellman2,3,11
11 affiliations
  1. 1Department of Biological Chemistry and Molecular Pharmacology, Blavatnik Institute, Harvard Medical School, Boston, MA 02115, USA
  2. 2Department of Cell Biology, Blavatnik Institute, Harvard Medical School, Boston, MA 02115, USA
  3. 3Department of Pediatric Oncology, Dana-Farber Cancer Institute, and Boston Children’s Hospital, Boston, MA 02215, USA
  4. 4Department of Human Genetics, University of Michigan Medical School, Ann Arbor, MI 48109, USA
  5. 5Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109, USA
  6. 6Generate:Biomedicines, Boston, MA, USA
  7. 7Arrakis Therapeutics, Waltham, MA, USA
  8. 8Laboratory of Genome Integrity, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
  9. 9Present Address: Department of Biochemistry and Molecular Biophysics, Washington University in St. Louis, St. Louis, MO 63110, USA
  10. 10Molecular Genetics, Department of Biology, RPTU University Kaiserslautern-Landau, Kaiserslautern, Germany
  11. 11Howard Hughes Medical Institute
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Abstract

Cells entering mitosis with incompletely replicated DNA face catastrophic chromosome segregation failure. During interphase, the replisome-associated E3 ubiquitin ligase TRAIP ubiquitylates barriers in front of the fork to allow replisome progression. In mitosis, TRAIP is reprogrammed from a trans-acting to a cis-acting ligase that can ubiquitylate the replisome itself. This enables the processing of unreplicated DNA by promoting replisome disassembly, fork breakage, and joining of the broken chromosome arms. Here, we describe a mechanism for this reprogramming: The adenosine triphosphatase transcription termination factor 2 (TTF2) is recruited to the replisome, where its noncatalytic N-terminal domain tethers cyclin B-cyclin-dependent kinase 1-phosphorylated TRAIP to the leading strand DNA polymerase ε in a geometry that allows replisome ubiquitylation. Thus, a phosphoregulated architectural switch alters replisome organization in mitosis to safeguard genome integrity before chromosome segregation.

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Cite

BibTeXRIS
BibTeX
@article{can2026cdk1,
  title = {{A CDK1 phospho-switch reprograms TRAIP to unload replisomes in mitosis}},
  author = {Geylani Can and Maksym Shyian and Archana Krishnamoorthy and Samreen Ahmed and Yang Lim and Alex Wu and Raphael Pavani and Manal S. Zaher and André Nussenzweig and Markus Räschle and Thomas E. Wilson and Thomas W. Glover and Johannes C. Walter and David S. Pellman},
  journal = {Science},
  year = {2026},
  month = jul,
  doi = {10.1126/science.aeh1834},
  url = {https://doi.org/10.1126/science.aeh1834},
  note = {CC BY},
}
RIS
TY  - JOUR
TI  - A CDK1 phospho-switch reprograms TRAIP to unload replisomes in mitosis
AU  - Geylani Can
AU  - Maksym Shyian
AU  - Archana Krishnamoorthy
AU  - Samreen Ahmed
AU  - Yang Lim
AU  - Alex Wu
AU  - Raphael Pavani
AU  - Manal S. Zaher
AU  - André Nussenzweig
AU  - Markus Räschle
AU  - Thomas E. Wilson
AU  - Thomas W. Glover
AU  - Johannes C. Walter
AU  - David S. Pellman
PY  - 2026
DA  - 2026/07/02
JO  - Science
DO  - 10.1126/science.aeh1834
UR  - https://doi.org/10.1126/science.aeh1834
AB  - Cells entering mitosis with incompletely replicated DNA face catastrophic chromosome segregation failure. During interphase, the replisome-associated E3 ubiquitin ligase TRAIP ubiquitylates barriers in front of the fork to allow replisome progression. In mitosis, TRAIP is reprogrammed from a trans-acting to a cis-acting ligase that can ubiquitylate the replisome itself. This enables the processing of unreplicated DNA by promoting replisome disassembly, fork breakage, and joining of the broken chromosome arms. Here, we describe a mechanism for this reprogramming: The adenosine triphosphatase transcription termination factor 2 (TTF2) is recruited to the replisome, where its noncatalytic N-terminal domain tethers cyclin B-cyclin-dependent kinase 1-phosphorylated TRAIP to the leading strand DNA polymerase ε in a geometry that allows replisome ubiquitylation. Thus, a phosphoregulated architectural switch alters replisome organization in mitosis to safeguard genome integrity before chromosome segregation.
SN  - 0036-8075
SN  - 0193-4511
SN  - 1095-9203
ER  -