The ATR-Activation Domain of TopBP1 Is Required for the Suppression of Origin Firing during the S Phase

Sokka, Miiko; Koalick, Dennis; Hemmerich, Peter; Syväoja, Juhani E.; Pospiech, Helmut

doi:10.3390/ijms19082376

Cited by 14 publications

(15 citation statements)

References 38 publications

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“…ATR and CHK1 signaling could be initiated by TOPBP1 that is associated with CMG. In agreement with this hypothesis, the ATR-activating domain of TOPBP1 was recently found to play a role in origin suppression during the S phase (46). Recent findings by Saldivar et al (45) document ATR signaling suppressing CDK1 activity in the S phase and specifically at the S/G2 transition in unperturbed cells.…”

Section: Discussionsupporting

confidence: 59%

An ATR and CHK1 kinase signaling mechanism that limits origin firing during unperturbed DNA replication

Moiseeva

Yin

Calderon

et al. 2019

Proc. Natl. Acad. Sci. U.S.A.

121

114

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DNA damage-induced signaling by ATR and CHK1 inhibits DNA replication, stabilizes stalled and collapsed replication forks, and mediates the repair of multiple classes of DNA lesions. We and others have shown that ATR kinase inhibitors, three of which are currently undergoing clinical trials, induce excessive origin firing during unperturbed DNA replication, indicating that ATR kinase activity limits replication initiation in the absence of damage. However, the origins impacted and the underlying mechanism(s) have not been described. Here, we show that unperturbed DNA replication is associated with a low level of ATR and CHK1 kinase signaling and that inhibition of this signaling induces dormant origin firing at sites of ongoing replication throughout the S phase. We show that ATR and CHK1 kinase inhibitors induce RIF1 Ser2205 phosphorylation in a CDK1-dependent manner, which disrupts an interaction between RIF1 and PP1 phosphatase. Thus, ATR and CHK1 signaling suppresses CDK1 kinase activity throughout the S phase and stabilizes an interaction between RIF1 and PP1 in replicating cells. PP1 dephosphorylates key CDC7 and CDK2 kinase substrates to inhibit the assembly and activation of the replicative helicase. This mechanism limits origin firing during unperturbed DNA replication in human cells.

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Section: Discussionsupporting

confidence: 59%

An ATR and CHK1 kinase signaling mechanism that limits origin firing during unperturbed DNA replication

Moiseeva

Yin

Calderon

et al. 2019

Proc. Natl. Acad. Sci. U.S.A.

121

114

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show abstract

“…Moreover, a recent study found that an ATR inhibitor not only induced unscheduled origin firing, but also revealed another mechanism of origin regulation through a Cdc7-dependent phosphorylation of GINS [ 128 ]. Finally, a very recent study found that the ATR-activation domain of TOPBP1 is required to suppress origin firing during the S phase [ 129 ], further supporting an important role for the ATR–Chk1 pathway in regulating the activation of origins.…”

Section: Regulation Of Dormant Origins: a Passive Or Active Mechanmentioning

confidence: 90%

The Protective Role of Dormant Origins in Response to Replicative Stress

Courtot

Hoffmann

Bergoglio

2018

IJMS

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Genome stability requires tight regulation of DNA replication to ensure that the entire genome of the cell is duplicated once and only once per cell cycle. In mammalian cells, origin activation is controlled in space and time by a cell-specific and robust program called replication timing. About 100,000 potential replication origins form on the chromatin in the gap 1 (G1) phase but only 20–30% of them are active during the DNA replication of a given cell in the synthesis (S) phase. When the progress of replication forks is slowed by exogenous or endogenous impediments, the cell must activate some of the inactive or “dormant” origins to complete replication on time. Thus, the many origins that may be activated are probably key to protect the genome against replication stress. This review aims to discuss the role of these dormant origins as safeguards of the human genome during replicative stress.

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“…In quiescent cells that underwent HS, 4% of the cells stayed at the S phase whereas HS-treated proliferating culture had 14% cells in the S phase. Most reports on ATR function link ATR to the important role during the S phase [48–50]. Culture with low cell number in the S phase is more resistant to damage, and ATR expression is not required for DNA damage repair.…”

Section: Discussionmentioning

confidence: 99%

Quiescent Human Mesenchymal Stem Cells Are More Resistant to Heat Stress than Cycling Cells

Алексеенко

Шилина

Lyublinskaya

et al. 2018

Stem Cells International

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Quiescence is the prevailing state of many cell types under homeostatic conditions. Yet, surprisingly, little is known about how quiescent cells respond to environmental challenges. The aim of the present study is to compare stress responses of cycling and quiescent mesenchymal stem cells (MSC). Human endometrial mesenchymal cells (eMSС) were employed as adult stem cells. eMSC quiescence was modeled by serum starvation. Sublethal heat shock (HS) was used as a stress factor. Both quiescent and cycling cells were heated at 45°C for 30 min and then returned to standard culture conditions for their recovery. HS response was monitored by DNA damage response, stress-induced premature senescence (SIPS), cell proliferation activity, and oxidative metabolism. It has been found that quiescent cells repair DNA more rapidly, resume proliferation, and undergo SIPS less than proliferating cells. HS-enforced ROS production in heated cycling cells was accompanied with increased expression of genes regulating redox-active proteins. Quiescent cells exposed to HS did not intensify the ROS production, and genes involved in antioxidant defense were mostly silent. Altogether, the results have shown that quiescent cells are more resistant to heat stress than cycling cells. Next-generation sequencing (NGS) demonstrates that HS-survived cells retain differentiation capacity and do not exhibit signs of spontaneous transformation.

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The ATR-Activation Domain of TopBP1 Is Required for the Suppression of Origin Firing during the S Phase

Cited by 14 publications

References 38 publications

An ATR and CHK1 kinase signaling mechanism that limits origin firing during unperturbed DNA replication

An ATR and CHK1 kinase signaling mechanism that limits origin firing during unperturbed DNA replication

The Protective Role of Dormant Origins in Response to Replicative Stress

Quiescent Human Mesenchymal Stem Cells Are More Resistant to Heat Stress than Cycling Cells

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