Regulation of ETAA1-mediated ATR activation couples DNA replication fidelity and genome stability

Divya Achuthankutty; Roshan Singh Thakur; Peter Haahr; Saskia Hoffmann; Alexandros P Drainas; Anna H Bizard; Joachim Weischenfeldt; Ian D Hickson; Niels Mailand

doi:10.1083/jcb.201905064

Regulation of ETAA1-mediated ATR activation couples DNA replication fidelity and genome stability

Divya Achuthankutty, Roshan Singh Thakur, Peter Haahr, Saskia Hoffmann, Alexandros P Drainas, Anna H Bizard, Joachim Weischenfeldt, Ian D Hickson, Niels Mailand

Molecular Aging Program

Abstract

The ATR kinase is a master regulator of the cellular response to DNA replication stress. Activation of ATR relies on dual pathways involving the TopBP1 and ETAA1 proteins, both of which harbor ATR-activating domains (AADs). However, the exact contribution of the recently discovered ETAA1 pathway to ATR signaling in different contexts remains poorly understood. Here, using an unbiased CRISPR-Cas9-based genome-scale screen, we show that the ATR-stimulating function of ETAA1 becomes indispensable for cell fitness and chromosome stability when the fidelity of DNA replication is compromised. We demonstrate that the ATR-activating potential of ETAA1 is controlled by cell cycle- and replication stress-dependent phosphorylation of highly conserved residues within its AAD, and that the stimulatory impact of these modifications is required for the ability of ETAA1 to prevent mitotic chromosome abnormalities following replicative stress. Our findings suggest an important role of ETAA1 in protecting against genome instability arising from incompletely duplicated DNA via regulatory control of its ATR-stimulating potential.

Original language	English
Article number	3943
Journal	The Journal of Cell Biology
Volume	218
Issue number	12
Number of pages	11
ISSN	0021-9525
DOIs	https://doi.org/10.1083/jcb.201905064
Publication status	Published - 2 Dec 2019

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title = "Regulation of ETAA1-mediated ATR activation couples DNA replication fidelity and genome stability",

abstract = "The ATR kinase is a master regulator of the cellular response to DNA replication stress. Activation of ATR relies on dual pathways involving the TopBP1 and ETAA1 proteins, both of which harbor ATR-activating domains (AADs). However, the exact contribution of the recently discovered ETAA1 pathway to ATR signaling in different contexts remains poorly understood. Here, using an unbiased CRISPR-Cas9-based genome-scale screen, we show that the ATR-stimulating function of ETAA1 becomes indispensable for cell fitness and chromosome stability when the fidelity of DNA replication is compromised. We demonstrate that the ATR-activating potential of ETAA1 is controlled by cell cycle- and replication stress-dependent phosphorylation of highly conserved residues within its AAD, and that the stimulatory impact of these modifications is required for the ability of ETAA1 to prevent mitotic chromosome abnormalities following replicative stress. Our findings suggest an important role of ETAA1 in protecting against genome instability arising from incompletely duplicated DNA via regulatory control of its ATR-stimulating potential.",

author = "Divya Achuthankutty and Thakur, {Roshan Singh} and Peter Haahr and Saskia Hoffmann and Drainas, {Alexandros P} and Bizard, {Anna H} and Joachim Weischenfeldt and Hickson, {Ian D} and Niels Mailand",

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doi = "10.1083/jcb.201905064",

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AU - Achuthankutty, Divya

AU - Thakur, Roshan Singh

AU - Haahr, Peter

AU - Hoffmann, Saskia

AU - Drainas, Alexandros P

AU - Bizard, Anna H

AU - Weischenfeldt, Joachim

AU - Hickson, Ian D

AU - Mailand, Niels

PY - 2019/12/2

Y1 - 2019/12/2

N2 - The ATR kinase is a master regulator of the cellular response to DNA replication stress. Activation of ATR relies on dual pathways involving the TopBP1 and ETAA1 proteins, both of which harbor ATR-activating domains (AADs). However, the exact contribution of the recently discovered ETAA1 pathway to ATR signaling in different contexts remains poorly understood. Here, using an unbiased CRISPR-Cas9-based genome-scale screen, we show that the ATR-stimulating function of ETAA1 becomes indispensable for cell fitness and chromosome stability when the fidelity of DNA replication is compromised. We demonstrate that the ATR-activating potential of ETAA1 is controlled by cell cycle- and replication stress-dependent phosphorylation of highly conserved residues within its AAD, and that the stimulatory impact of these modifications is required for the ability of ETAA1 to prevent mitotic chromosome abnormalities following replicative stress. Our findings suggest an important role of ETAA1 in protecting against genome instability arising from incompletely duplicated DNA via regulatory control of its ATR-stimulating potential.

AB - The ATR kinase is a master regulator of the cellular response to DNA replication stress. Activation of ATR relies on dual pathways involving the TopBP1 and ETAA1 proteins, both of which harbor ATR-activating domains (AADs). However, the exact contribution of the recently discovered ETAA1 pathway to ATR signaling in different contexts remains poorly understood. Here, using an unbiased CRISPR-Cas9-based genome-scale screen, we show that the ATR-stimulating function of ETAA1 becomes indispensable for cell fitness and chromosome stability when the fidelity of DNA replication is compromised. We demonstrate that the ATR-activating potential of ETAA1 is controlled by cell cycle- and replication stress-dependent phosphorylation of highly conserved residues within its AAD, and that the stimulatory impact of these modifications is required for the ability of ETAA1 to prevent mitotic chromosome abnormalities following replicative stress. Our findings suggest an important role of ETAA1 in protecting against genome instability arising from incompletely duplicated DNA via regulatory control of its ATR-stimulating potential.

U2 - 10.1083/jcb.201905064

DO - 10.1083/jcb.201905064

M3 - Journal article

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SN - 0021-9525

VL - 218

JO - Journal of Cell Biology

JF - Journal of Cell Biology

IS - 12

M1 - 3943

ER -

Regulation of ETAA1-mediated ATR activation couples DNA replication fidelity and genome stability

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