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

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

Standard

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; O'Hanlon, Karen Arabella; Patzke, Sebastian; Holmberg, Christian Henrik; Mejlvang, Jakob; Groth, Anja; Nielsen, Olaf; Syljuåsen, Randi Gussgard; Sørensen, Claus Storgaard.

In: Molecular and Cellular Biology, Vol. 32, No. 20, 2012, p. 4226-4236.

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

Harvard

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

APA

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

Vancouver

Beck H, Nähse-Kumpf V, Larsen MSY, O'Hanlon KA, Patzke S, Holmberg CH et al. Cyclin-dependent kinase suppression by WEE1 kinase protects the genome through control of replication initiation and nucleotide consumption. Molecular and Cellular Biology. 2012;32(20):4226-4236. https://doi.org/10.1128/MCB.00412-12

Author

Beck, Halfdan ; Nähse-Kumpf, Viola ; Larsen, Marie Sofie Yoo ; O'Hanlon, Karen Arabella ; Patzke, Sebastian ; Holmberg, Christian Henrik ; Mejlvang, Jakob ; Groth, Anja ; Nielsen, Olaf ; Syljuåsen, Randi Gussgard ; Sørensen, Claus Storgaard. / Cyclin-dependent kinase suppression by WEE1 kinase protects the genome through control of replication initiation and nucleotide consumption. In: Molecular and Cellular Biology. 2012 ; Vol. 32, No. 20. pp. 4226-4236.

Bibtex

@article{c38cd35ddd6b4742bbf489bd563bfc95,
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. We now show that elevation of CDK activity by inhibiting WEE1 kinase rapidly increases initiation of replication. This leads to nucleotide shortage and reduces replication fork speed, which is followed by SLX4/MUS81-mediated DNA double-strand breakage. Fork speed is normalized and DNA double-strand break (DSB) formation is suppressed when CDT1, a key factor for replication initiation, is depleted. Furthermore, addition of nucleosides counteracts the effects of unscheduled CDK activity on fork speed and DNA DSB formation. Finally, we show that WEE1 regulates the IR-induced S phase checkpoint, consistent with its role in control of replication initiation. In conclusion, these results suggest that deregulated CDK activity, 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}",
year = "2012",
doi = "10.1128/MCB.00412-12",
language = "English",
volume = "32",
pages = "4226--4236",
journal = "Molecular and Cellular Biology",
issn = "0270-7306",
publisher = "American Society for Microbiology",
number = "20",

}

RIS

TY - JOUR

T1 - Cyclin-dependent kinase suppression by WEE1 kinase protects the genome through control of replication initiation and nucleotide consumption

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

Y1 - 2012

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. We now show that elevation of CDK activity by inhibiting WEE1 kinase rapidly increases initiation of replication. This leads to nucleotide shortage and reduces replication fork speed, which is followed by SLX4/MUS81-mediated DNA double-strand breakage. Fork speed is normalized and DNA double-strand break (DSB) formation is suppressed when CDT1, a key factor for replication initiation, is depleted. Furthermore, addition of nucleosides counteracts the effects of unscheduled CDK activity on fork speed and DNA DSB formation. Finally, we show that WEE1 regulates the IR-induced S phase checkpoint, consistent with its role in control of replication initiation. In conclusion, these results suggest that deregulated CDK activity, 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. We now show that elevation of CDK activity by inhibiting WEE1 kinase rapidly increases initiation of replication. This leads to nucleotide shortage and reduces replication fork speed, which is followed by SLX4/MUS81-mediated DNA double-strand breakage. Fork speed is normalized and DNA double-strand break (DSB) formation is suppressed when CDT1, a key factor for replication initiation, is depleted. Furthermore, addition of nucleosides counteracts the effects of unscheduled CDK activity on fork speed and DNA DSB formation. Finally, we show that WEE1 regulates the IR-induced S phase checkpoint, consistent with its role in control of replication initiation. In conclusion, these results suggest that deregulated CDK activity, 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

VL - 32

SP - 4226

EP - 4236

JO - Molecular and Cellular Biology

JF - Molecular and Cellular Biology

SN - 0270-7306

IS - 20

ER -

ID: 40462431