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Structural mechanism of TOPBP1 activating the ATR-ATRIP replication checkpoint kinase
Buren Li1,2, Ayat Yaseen1, Nikola P Pavletich3
1Structural Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
Nature Structural & Molecular Biology
|July 23, 2026
Summary
The ATR-ATRIP complex
Area of Science:
- Molecular Biology
- Cell Biology
- Structural Biology
Background:
- The ATR-ATRIP complex is crucial for maintaining genomic stability during DNA replication and responding to replication stress.
- TOPBP1 and ETAA1 proteins activate ATR-ATRIP, controlling distinct signaling pathways essential for cell cycle progression.
- The precise mechanisms by which TOPBP1 and ETAA1 activate ATR-ATRIP remained unclear.
Purpose of the Study:
- To elucidate the structural mechanisms by which TOPBP1 and ETAA1 activate the ATR-ATRIP complex.
- To understand how different activation modes contribute to distinct cellular outcomes of ATR signaling.
Main Methods:
- Cryo-electron microscopy (cryo-EM) was used to determine the structures of the human ATR-ATRIP complex bound to the TOPBP1 ATR-activating domain (AAD) and the ETAA1 AAD.
- Structural analysis focused on the binding interfaces and conformational changes induced in ATR-ATRIP.
Main Results:
- The 3.0-Å cryo-EM structure revealed that TOPBP1 activates ATR-ATRIP through a global conformational change, allosterically repositioning active site residues.
- The 3.3-Å structure of the ATR-ATRIP-ETAA1 AAD complex showed a distinct binding mode compared to TOPBP1.
- These distinct binding modes suggest differential regulation of ATR-ATRIP activity.
Conclusions:
- TOPBP1 and ETAA1 activate ATR-ATRIP via distinct structural mechanisms.
- The differential activation modes likely contribute to the specific roles of ATR signaling in different cellular contexts, such as S-phase checkpoint control and mitotic progression.
- Understanding these mechanisms provides insight into maintaining genomic integrity.
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