An intrinsic S/G2 checkpoint enforced by ATR
An additional cell cycle checkpointCell division is controlled by checkpoints that regulate the temporal order of the cell cycle phases, including the G1/S, G2/M, and metaphase/anaphase transitions. Yet there are no known control mechanisms for a fourth fundamental transition—the S/G2 transition. Sa...
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| Veröffentlicht in: | Science (American Association for the Advancement of Science) 2018-08, Vol.361 (6404), p.806-810 |
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| creator | Saldivar, Joshua C Hamperl Stephan Bocek, Michael J Chung, Mingyu Bass, Thomas E Cisneros-Soberanis Fernanda Samejima Kumiko Xie Linfeng Paulson, James R Earnshaw, William C Cortez, David Meyer, Tobias Cimprich, Karlene A |
| description | An additional cell cycle checkpointCell division is controlled by checkpoints that regulate the temporal order of the cell cycle phases, including the G1/S, G2/M, and metaphase/anaphase transitions. Yet there are no known control mechanisms for a fourth fundamental transition—the S/G2 transition. Saldivar et al. report a switchlike control mechanism that regulates the S/G2 transition. The checkpoint kinase ATR senses ongoing DNA replication in S phase and represses the mitotic transcriptional network, ensuring that DNA replication in S phase is completed before mitosis.Science, this issue p. 806The 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. |
| doi_str_mv | 10.1126/science.aap9346 |
| format | Article |
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Yet there are no known control mechanisms for a fourth fundamental transition—the S/G2 transition. Saldivar et al. report a switchlike control mechanism that regulates the S/G2 transition. The checkpoint kinase ATR senses ongoing DNA replication in S phase and represses the mitotic transcriptional network, ensuring that DNA replication in S phase is completed before mitosis.Science, this issue p. 806The 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.</description><identifier>ISSN: 0036-8075</identifier><identifier>ISSN: 1095-9203</identifier><identifier>EISSN: 1095-9203</identifier><identifier>DOI: 10.1126/science.aap9346</identifier><identifier>PMID: 30139873</identifier><language>eng</language><publisher>Washington: The American Association for the Advancement of Science</publisher><subject>Anaphase ; Ataxia ; Ataxia telangiectasia ; Cell cycle ; Cell division ; Cyclin-dependent kinase ; Cyclin-dependent kinases ; Deoxyribonucleic acid ; Deregulation ; DNA ; DNA biosynthesis ; DNA damage ; Gene duplication ; Genomes ; Metaphase ; Mitosis ; Phase transitions ; Phosphorylation ; Replication ; S phase ; Temporal variations ; Transcription</subject><ispartof>Science (American Association for the Advancement of Science), 2018-08, Vol.361 (6404), p.806-810</ispartof><rights>Copyright © 2018 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works</rights><rights>Copyright © 2018 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>230,314,776,780,881,27901,27902</link.rule.ids></links><search><creatorcontrib>Saldivar, Joshua C</creatorcontrib><creatorcontrib>Hamperl Stephan</creatorcontrib><creatorcontrib>Bocek, Michael J</creatorcontrib><creatorcontrib>Chung, Mingyu</creatorcontrib><creatorcontrib>Bass, Thomas E</creatorcontrib><creatorcontrib>Cisneros-Soberanis Fernanda</creatorcontrib><creatorcontrib>Samejima Kumiko</creatorcontrib><creatorcontrib>Xie Linfeng</creatorcontrib><creatorcontrib>Paulson, James R</creatorcontrib><creatorcontrib>Earnshaw, William C</creatorcontrib><creatorcontrib>Cortez, David</creatorcontrib><creatorcontrib>Meyer, Tobias</creatorcontrib><creatorcontrib>Cimprich, Karlene A</creatorcontrib><title>An intrinsic S/G2 checkpoint enforced by ATR</title><title>Science (American Association for the Advancement of Science)</title><description>An additional cell cycle checkpointCell division is controlled by checkpoints that regulate the temporal order of the cell cycle phases, including the G1/S, G2/M, and metaphase/anaphase transitions. Yet there are no known control mechanisms for a fourth fundamental transition—the S/G2 transition. Saldivar et al. report a switchlike control mechanism that regulates the S/G2 transition. The checkpoint kinase ATR senses ongoing DNA replication in S phase and represses the mitotic transcriptional network, ensuring that DNA replication in S phase is completed before mitosis.Science, this issue p. 806The 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.</description><subject>Anaphase</subject><subject>Ataxia</subject><subject>Ataxia telangiectasia</subject><subject>Cell cycle</subject><subject>Cell division</subject><subject>Cyclin-dependent kinase</subject><subject>Cyclin-dependent kinases</subject><subject>Deoxyribonucleic acid</subject><subject>Deregulation</subject><subject>DNA</subject><subject>DNA biosynthesis</subject><subject>DNA damage</subject><subject>Gene duplication</subject><subject>Genomes</subject><subject>Metaphase</subject><subject>Mitosis</subject><subject>Phase transitions</subject><subject>Phosphorylation</subject><subject>Replication</subject><subject>S phase</subject><subject>Temporal 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Science)</jtitle><date>2018-08-24</date><risdate>2018</risdate><volume>361</volume><issue>6404</issue><spage>806</spage><epage>810</epage><pages>806-810</pages><issn>0036-8075</issn><issn>1095-9203</issn><eissn>1095-9203</eissn><abstract>An additional cell cycle checkpointCell division is controlled by checkpoints that regulate the temporal order of the cell cycle phases, including the G1/S, G2/M, and metaphase/anaphase transitions. Yet there are no known control mechanisms for a fourth fundamental transition—the S/G2 transition. Saldivar et al. report a switchlike control mechanism that regulates the S/G2 transition. The checkpoint kinase ATR senses ongoing DNA replication in S phase and represses the mitotic transcriptional network, ensuring that DNA replication in S phase is completed before mitosis.Science, this issue p. 806The 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.</abstract><cop>Washington</cop><pub>The American Association for the Advancement of Science</pub><pmid>30139873</pmid><doi>10.1126/science.aap9346</doi><tpages>5</tpages></addata></record> |
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| source | American Association for the Advancement of Science; Jstor Complete Legacy |
| subjects | Anaphase Ataxia Ataxia telangiectasia Cell cycle Cell division Cyclin-dependent kinase Cyclin-dependent kinases Deoxyribonucleic acid Deregulation DNA DNA biosynthesis DNA damage Gene duplication Genomes Metaphase Mitosis Phase transitions Phosphorylation Replication S phase Temporal variations Transcription |
| title | An intrinsic S/G2 checkpoint enforced by ATR |
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