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 - Funding Information:
We thank F. Ochs, J. Ferrell, and the Cimprich laboratory for comments on the manuscript. This work was supported by grants from the NIH to K.A.C. (ES016486), D.C. (CA102729), and T.M. (GM127026); the Wellcome Fund (107022 and 203149) to W.C.E.; the American Cancer Society (PF-15-165-01–DMC) and the Burroughs Wellcome Fund Postdoctoral Enrichment Program to J.C.S.; the German Research Foundation DFG (HA 6996/1-1) to S.H.; and by a Mexican Government CONACYT fellowship to F.C.-S. Author contributions: J.C.S. W.C.E. D.C.
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 -