A CDK1 phospho-switch reprograms TRAIP to unload replisomes in mitosis.
Geylani Can1,2,3, Maksym Shyian3, Archana Krishnamoorthy1,2
1Department of Cell Biology, Blavatnik Institute, Harvard Medical School, Boston, MA, USA.
Science (New York, N.Y.)
|July 2, 2026
Summary
Unreplicated DNA in mitosis causes cell failure. A protein called TRAIP is reprogrammed to disassemble the replisome, preventing chromosome segregation errors and safeguarding genome integrity.
Area of Science:
- Molecular Biology
- Cell Biology
- Genetics
Background:
- Cells require complete DNA replication before mitosis to prevent chromosome segregation failure.
- The E3 ubiquitin ligase TRAIP normally facilitates replisome progression during interphase by ubiquitylating fork barriers.
- During mitosis, TRAIP's function shifts to process incompletely replicated DNA, crucial for genome stability.
Purpose of the Study:
- To elucidate the mechanism by which TRAIP is reprogrammed in mitosis.
- To understand how TRAIP processes unreplicated DNA during cell division.
- To identify factors involved in altering replisome organization for genome integrity.
Main Methods:
- Investigated the role of the ATPase TTF2 in TRAIP reprogramming.
- Utilized biochemical assays to study protein interactions at the replisome.
- Examined the effect of Cyclin B-CDK1 phosphorylation on TRAIP localization and activity.
Main Results:
- TTF2 recruits and tethers phosphorylated TRAIP to DNA polymerase ε at the replisome.
- This interaction enables TRAIP to ubiquitylate the replisome in mitosis.
- The process promotes replisome disassembly, fork breakage, and chromosome arm joining.
Conclusions:
- A phospho-regulated architectural switch involving TTF2 reprograms TRAIP in mitosis.
- This switch alters replisome organization to ensure proper processing of unreplicated DNA.
- The mechanism safeguards genome integrity before chromosome segregation.
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