Cyclin-dependent kinase suppression by WEE1 kinase protects the genome through control of replication initiation and nucleotide consumption

Halfdan Beck; Viola Nähse-Kumpf; Marie Sofie Yoo Larsen; Karen Arabella O'Hanlon; Sebastian Patzke; Christian Henrik Holmberg; Jakob Mejlvang; Anja Groth; Olaf Nielsen; Randi Gussgard Syljuåsen; Claus Storgaard Sørensen

doi:10.1128/MCB.00412-12

Cyclin-dependent kinase suppression by WEE1 kinase protects the genome through control of replication initiation and nucleotide consumption

Halfdan Beck, Viola Nähse-Kumpf, Marie Sofie Yoo Larsen, Karen Arabella O'Hanlon, Sebastian Patzke, Christian Henrik Holmberg, Jakob Mejlvang, Anja Groth, Olaf Nielsen, Randi Gussgard Syljuåsen, Claus Storgaard Sørensen

Functional Genomics

150 Citations (Scopus)

Abstract

Activation of oncogenes or inhibition of WEE1 kinase deregulates cyclin-dependent kinase (CDK) activity and leads to replication stress; however, the underlying mechanism is not understood.Wenow show that elevation ofCDKactivity by inhibition of WEE1 kinase rapidly increases initiation of replication. This leads to nucleotide shortage and reduces replication fork speed, which is followed by SLX4/MUS81-mediatedDNAdouble-strand breakage. Fork speed is normalized andDNAdouble-strand break (DSB) formation is suppressed when CDT1, a key factor for replication initiation, is depleted. Furthermore, addition of nucleosides counteracts the effects of unscheduledCDKactivity on fork speed andDNADSB formation. Finally, we show that WEE1 regulates the ionizing radiation (IR)-induced S-phase checkpoint, consistent with its role in control of replication initiation. In conclusion, these results suggest that deregulatedCDKactivity, such as that occurring following inhibition of WEE1 kinase or activation of oncogenes, induces replication stress and loss of genomic integrity through increased firing of replication origins and subsequent nucleotide shortage.

Original language	English
Journal	Molecular and Cellular Biology
Volume	32
Issue number	20
Pages (from-to)	4226-4236
Number of pages	11
ISSN	0270-7306
DOIs	https://doi.org/10.1128/MCB.00412-12
Publication status	Published - Oct 2012

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Beck, H., Nähse-Kumpf, V., Larsen, M. S. Y., O'Hanlon, K. A., Patzke, S., Holmberg, C. H., Mejlvang, J., Groth, A., Nielsen, O., Syljuåsen, R. G., & Sørensen, C. S. (2012). Cyclin-dependent kinase suppression by WEE1 kinase protects the genome through control of replication initiation and nucleotide consumption. Molecular and Cellular Biology, 32(20), 4226-4236. https://doi.org/10.1128/MCB.00412-12

Cyclin-dependent kinase suppression by WEE1 kinase protects the genome through control of replication initiation and nucleotide consumption. / Beck, Halfdan; Nähse-Kumpf, Viola; Larsen, Marie Sofie Yoo et al.
In: Molecular and Cellular Biology, Vol. 32, No. 20, 10.2012, p. 4226-4236.

Research output: Contribution to journal › Journal article › Research › peer-review

Beck, H, Nähse-Kumpf, V, Larsen, MSY, O'Hanlon, KA, Patzke, S, Holmberg, CH, Mejlvang, J, Groth, A , Nielsen, O, Syljuåsen, RG & Sørensen, CS 2012, 'Cyclin-dependent kinase suppression by WEE1 kinase protects the genome through control of replication initiation and nucleotide consumption', Molecular and Cellular Biology, vol. 32, no. 20, pp. 4226-4236. https://doi.org/10.1128/MCB.00412-12

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title = "Cyclin-dependent kinase suppression by WEE1 kinase protects the genome through control of replication initiation and nucleotide consumption",

abstract = "Activation of oncogenes or inhibition of WEE1 kinase deregulates cyclin-dependent kinase (CDK) activity and leads to replication stress; however, the underlying mechanism is not understood.Wenow show that elevation ofCDKactivity by inhibition of WEE1 kinase rapidly increases initiation of replication. This leads to nucleotide shortage and reduces replication fork speed, which is followed by SLX4/MUS81-mediatedDNAdouble-strand breakage. Fork speed is normalized andDNAdouble-strand break (DSB) formation is suppressed when CDT1, a key factor for replication initiation, is depleted. Furthermore, addition of nucleosides counteracts the effects of unscheduledCDKactivity on fork speed andDNADSB formation. Finally, we show that WEE1 regulates the ionizing radiation (IR)-induced S-phase checkpoint, consistent with its role in control of replication initiation. In conclusion, these results suggest that deregulatedCDKactivity, such as that occurring following inhibition of WEE1 kinase or activation of oncogenes, induces replication stress and loss of genomic integrity through increased firing of replication origins and subsequent nucleotide shortage.",

author = "Halfdan Beck and Viola N{\"a}hse-Kumpf and Larsen, {Marie Sofie Yoo} and O'Hanlon, {Karen Arabella} and Sebastian Patzke and Holmberg, {Christian Henrik} and Jakob Mejlvang and Anja Groth and Olaf Nielsen and Sylju{\aa}sen, {Randi Gussgard} and S{\o}rensen, {Claus Storgaard}",

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AU - Beck, Halfdan

AU - Nähse-Kumpf, Viola

AU - Larsen, Marie Sofie Yoo

AU - O'Hanlon, Karen Arabella

AU - Patzke, Sebastian

AU - Holmberg, Christian Henrik

AU - Mejlvang, Jakob

AU - Groth, Anja

AU - Nielsen, Olaf

AU - Syljuåsen, Randi Gussgard

AU - Sørensen, Claus Storgaard

PY - 2012/10

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N2 - Activation of oncogenes or inhibition of WEE1 kinase deregulates cyclin-dependent kinase (CDK) activity and leads to replication stress; however, the underlying mechanism is not understood.Wenow show that elevation ofCDKactivity by inhibition of WEE1 kinase rapidly increases initiation of replication. This leads to nucleotide shortage and reduces replication fork speed, which is followed by SLX4/MUS81-mediatedDNAdouble-strand breakage. Fork speed is normalized andDNAdouble-strand break (DSB) formation is suppressed when CDT1, a key factor for replication initiation, is depleted. Furthermore, addition of nucleosides counteracts the effects of unscheduledCDKactivity on fork speed andDNADSB formation. Finally, we show that WEE1 regulates the ionizing radiation (IR)-induced S-phase checkpoint, consistent with its role in control of replication initiation. In conclusion, these results suggest that deregulatedCDKactivity, such as that occurring following inhibition of WEE1 kinase or activation of oncogenes, induces replication stress and loss of genomic integrity through increased firing of replication origins and subsequent nucleotide shortage.

AB - Activation of oncogenes or inhibition of WEE1 kinase deregulates cyclin-dependent kinase (CDK) activity and leads to replication stress; however, the underlying mechanism is not understood.Wenow show that elevation ofCDKactivity by inhibition of WEE1 kinase rapidly increases initiation of replication. This leads to nucleotide shortage and reduces replication fork speed, which is followed by SLX4/MUS81-mediatedDNAdouble-strand breakage. Fork speed is normalized andDNAdouble-strand break (DSB) formation is suppressed when CDT1, a key factor for replication initiation, is depleted. Furthermore, addition of nucleosides counteracts the effects of unscheduledCDKactivity on fork speed andDNADSB formation. Finally, we show that WEE1 regulates the ionizing radiation (IR)-induced S-phase checkpoint, consistent with its role in control of replication initiation. In conclusion, these results suggest that deregulatedCDKactivity, such as that occurring following inhibition of WEE1 kinase or activation of oncogenes, induces replication stress and loss of genomic integrity through increased firing of replication origins and subsequent nucleotide shortage.

U2 - 10.1128/MCB.00412-12

DO - 10.1128/MCB.00412-12

M3 - Journal article

C2 - 22907750

SN - 0270-7306

VL - 32

SP - 4226

EP - 4236

JO - Molecular and Cellular Biology

JF - Molecular and Cellular Biology

IS - 20

ER -

Cyclin-dependent kinase suppression by WEE1 kinase protects the genome through control of replication initiation and nucleotide consumption

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