Regulators of cyclin-dependent kinases are crucial for maintaining genome integrity in S phase

Halfdan Beck; Viola Nähse; Marie Sofie Yoo Larsen; Petra Groth; Trevor Clancy; Michael Lees; Mette Jørgensen; Thomas Helleday; Randi G Syljuåsen; Claus Storgaard Sørensen

doi:10.1083/jcb.200905059

Regulators of cyclin-dependent kinases are crucial for maintaining genome integrity in S phase

Halfdan Beck, Viola Nähse, Marie Sofie Yoo Larsen, Petra Groth, Trevor Clancy, Michael Lees, Mette Jørgensen, Thomas Helleday, Randi G Syljuåsen, Claus Storgaard Sørensen

121 Citations (Scopus)

Abstract

Maintenance of genome integrity is of critical importance to cells. To identify key regulators of genomic integrity, we screened a human cell line with a kinome small interfering RNA library. WEE1, a major regulator of mitotic entry, and CHK1 were among the genes identified. Both kinases are important negative regulators of CDK1 and -2. Strikingly, WEE1 depletion rapidly induced DNA damage in S phase in newly replicated DNA, which was accompanied by a marked increase in single-stranded DNA. This DNA damage is dependent on CDK1 and -2 as well as the replication proteins MCM2 and CDT1 but not CDC25A. Conversely, DNA damage after CHK1 inhibition is highly dependent on CDC25A. Furthermore, the inferior proliferation of CHK1-depleted cells is improved substantially by codepletion of CDC25A. We conclude that the mitotic kinase WEE1 and CHK1 jointly maintain balanced cellular control of Cdk activity during normal DNA replication, which is crucial to prevent the generation of harmful DNA lesions during replication.

Original language	English
Journal	Journal of Cell Biology
Volume	188
Issue number	5
Pages (from-to)	629-38
Number of pages	9
ISSN	0021-9525
DOIs	https://doi.org/10.1083/jcb.200905059
Publication status	Published - 8 Mar 2010

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title = "Regulators of cyclin-dependent kinases are crucial for maintaining genome integrity in S phase",

abstract = "Maintenance of genome integrity is of critical importance to cells. To identify key regulators of genomic integrity, we screened a human cell line with a kinome small interfering RNA library. WEE1, a major regulator of mitotic entry, and CHK1 were among the genes identified. Both kinases are important negative regulators of CDK1 and -2. Strikingly, WEE1 depletion rapidly induced DNA damage in S phase in newly replicated DNA, which was accompanied by a marked increase in single-stranded DNA. This DNA damage is dependent on CDK1 and -2 as well as the replication proteins MCM2 and CDT1 but not CDC25A. Conversely, DNA damage after CHK1 inhibition is highly dependent on CDC25A. Furthermore, the inferior proliferation of CHK1-depleted cells is improved substantially by codepletion of CDC25A. We conclude that the mitotic kinase WEE1 and CHK1 jointly maintain balanced cellular control of Cdk activity during normal DNA replication, which is crucial to prevent the generation of harmful DNA lesions during replication.",

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doi = "10.1083/jcb.200905059",

language = "English",

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T1 - Regulators of cyclin-dependent kinases are crucial for maintaining genome integrity in S phase

AU - Beck, Halfdan

AU - Nähse, Viola

AU - Larsen, Marie Sofie Yoo

AU - Groth, Petra

AU - Clancy, Trevor

AU - Lees, Michael

AU - Jørgensen, Mette

AU - Helleday, Thomas

AU - Syljuåsen, Randi G

AU - Sørensen, Claus Storgaard

PY - 2010/3/8

Y1 - 2010/3/8

N2 - Maintenance of genome integrity is of critical importance to cells. To identify key regulators of genomic integrity, we screened a human cell line with a kinome small interfering RNA library. WEE1, a major regulator of mitotic entry, and CHK1 were among the genes identified. Both kinases are important negative regulators of CDK1 and -2. Strikingly, WEE1 depletion rapidly induced DNA damage in S phase in newly replicated DNA, which was accompanied by a marked increase in single-stranded DNA. This DNA damage is dependent on CDK1 and -2 as well as the replication proteins MCM2 and CDT1 but not CDC25A. Conversely, DNA damage after CHK1 inhibition is highly dependent on CDC25A. Furthermore, the inferior proliferation of CHK1-depleted cells is improved substantially by codepletion of CDC25A. We conclude that the mitotic kinase WEE1 and CHK1 jointly maintain balanced cellular control of Cdk activity during normal DNA replication, which is crucial to prevent the generation of harmful DNA lesions during replication.

AB - Maintenance of genome integrity is of critical importance to cells. To identify key regulators of genomic integrity, we screened a human cell line with a kinome small interfering RNA library. WEE1, a major regulator of mitotic entry, and CHK1 were among the genes identified. Both kinases are important negative regulators of CDK1 and -2. Strikingly, WEE1 depletion rapidly induced DNA damage in S phase in newly replicated DNA, which was accompanied by a marked increase in single-stranded DNA. This DNA damage is dependent on CDK1 and -2 as well as the replication proteins MCM2 and CDT1 but not CDC25A. Conversely, DNA damage after CHK1 inhibition is highly dependent on CDC25A. Furthermore, the inferior proliferation of CHK1-depleted cells is improved substantially by codepletion of CDC25A. We conclude that the mitotic kinase WEE1 and CHK1 jointly maintain balanced cellular control of Cdk activity during normal DNA replication, which is crucial to prevent the generation of harmful DNA lesions during replication.

U2 - 10.1083/jcb.200905059

DO - 10.1083/jcb.200905059

M3 - Journal article

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SN - 0021-9525

VL - 188

SP - 629

EP - 638

JO - Journal of Cell Biology

JF - Journal of Cell Biology

IS - 5

ER -

Regulators of cyclin-dependent kinases are crucial for maintaining genome integrity in S phase

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