An intrinsic S/G2 checkpoint enforced by ATR.
Joshua C SaldivarStephan HamperlMichael J BocekMingyu ChungThomas E BassFernanda Cisneros-SoberanisKumiko SamejimaLinfeng XieJames R PaulsonWilliam C EarnshawDavid CortezTobias MeyerKarlene A CimprichPublished in: Science (New York, N.Y.) (2018)
The cell cycle is strictly ordered to ensure faithful genome duplication and chromosome segregation. Control mechanisms establish this order by dictating when a cell transitions from one phase to the next. Much is known about the control of the G1/S, G2/M, and metaphase/anaphase transitions, but thus far, no control mechanism has been identified for the S/G2 transition. Here we show that cells transactivate the mitotic gene network as they exit the S phase through a CDK1 (cyclin-dependent kinase 1)-directed FOXM1 phosphorylation switch. During normal DNA replication, the checkpoint kinase ATR (ataxia-telangiectasia and Rad3-related) is activated by ETAA1 to block this switch until the S phase ends. ATR inhibition prematurely activates FOXM1, deregulating the S/G2 transition and leading to early mitosis, underreplicated DNA, and DNA damage. Thus, ATR couples DNA replication with mitosis and preserves genome integrity by enforcing an S/G2 checkpoint.
Keyphrases
- cell cycle
- dna damage
- cell proliferation
- dna damage response
- dna repair
- genome wide
- protein kinase
- induced apoptosis
- copy number
- oxidative stress
- cell cycle arrest
- stem cells
- single molecule
- circulating tumor
- dna methylation
- cell therapy
- cell death
- pi k akt
- gene expression
- mesenchymal stem cells
- endoplasmic reticulum stress
- drug induced
- genome wide analysis