An intrinsic S/G₂ checkpoint enforced by ATR

Area of Science:

• Cell Biology
• Molecular Biology
• Genetics

Background:

• The cell cycle requires strict order for genome duplication and chromosome segregation.
• While G1/S, G2/M, and metaphase/anaphase transitions are well-understood, the S/G2 transition lacks a defined control mechanism.
• Faithful cell cycle progression is crucial for preventing genomic instability.

Purpose of the Study:

• To identify the control mechanism governing the S/G2 cell cycle transition.
• To elucidate the role of ATR and FOXM1 in regulating the S/G2 transition.
• To understand how DNA replication is coupled with mitosis.

Main Methods:

• Investigated the S/G2 transition using cell-based assays.
• Utilized CDK1 (cyclin-dependent kinase 1) and FOXM1 phosphorylation as key molecular markers.
• Examined the role of ATR (ataxia-telangiectasia and Rad3-related) and ETAA1 in checkpoint activation.
• Assessed the consequences of ATR inhibition on cell cycle progression and DNA integrity.

Main Results:

• Cells transactivate the mitotic gene network via a CDK1-directed FOXM1 phosphorylation switch upon exiting S phase.
• The checkpoint kinase ATR, activated by ETAA1 during DNA replication, inhibits this switch until S phase completion.
• ATR inhibition leads to premature FOXM1 activation, deregulating the S/G2 transition, causing early mitosis, underreplicated DNA, and DNA damage.

Conclusions:

• ATR couples DNA replication with mitosis by enforcing an S/G2 checkpoint.
• This ATR-mediated checkpoint is essential for preserving genome integrity.
• The identified mechanism highlights a novel regulatory pathway in cell cycle control.