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

TY - JOUR

T1 - Regulation of ETAA1-mediated ATR activation couples DNA replication fidelity and genome stability

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

C2 - 31615875

SN - 0021-9525

VL - 218

JO - The Journal of Cell Biology

JF - The Journal of Cell Biology

IS - 12

M1 - 3943

ER -