TY - JOUR
T1 - An intrinsic S/G2 checkpoint enforced by ATR
AU - Saldivar, Joshua C.
AU - Hamperl, Stephan
AU - Bocek, Michael J.
AU - Chung, Mingyu
AU - Bass, Thomas E.
AU - Cisneros-Soberanis, Fernanda
AU - Samejima, Kumiko
AU - Xie, Linfeng
AU - Paulson, James R.
AU - Earnshaw, William C.
AU - Cortez, David
AU - Meyer, Tobias
AU - Cimprich, Karlene A.
N1 - Publisher Copyright:
2017 © The Authors,
PY - 2018/8/24
Y1 - 2018/8/24
N2 - 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.
AB - 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.
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U2 - 10.1126/science.aap9346
DO - 10.1126/science.aap9346
M3 - Article
C2 - 30139873
AN - SCOPUS:85052145563
SN - 0036-8075
VL - 361
SP - 806
EP - 810
JO - Science
JF - Science
IS - 6404
ER -