http://www.cell.com/article/S2211124722013572/pdf

Coordinating transcription and replication to mitigate their conflicts in early Drosophila embryos

Abstract The ATR kinase, which coordinates cellular responses to DNA replication stress, is also essential for the proliferation of normal unstressed cells. Although its role in the replication stress response is well defined, the mechanisms by which ATR supports normal cell proliferation remain elusive. Here, we show that ATR is dispensable for the viability of G0-arrested naïve B cells. However, upon cytokine-induced proliferation, Atr-deficient B cells initiate DNA replication efficiently, but by mid-S phase they display dNTP depletion, fork stalling, and replication failure. Nonetheless, productive DNA replication and dNTP levels can be restored in Atr-deficient cells by suppressing origin firing, such as partial inhibition of CDC7 and CDK1 kinase activities. Together, these findings indicate that ATR supports the proliferation of normal unstressed cells by tempering the pace of origin firing during the early S phase to avoid exhaustion of dNTPs and importantly also other replication factors. 

/pdf/atr-kinase-supports-normal-proliferation-in-the-early-s-2djczu8o.pdf

ATR kinase supports normal proliferation in the early S phase by preventing replication resource exhaustion

Replication stress (RS) is a characteristic state of cancer cells as they tend to exchange precision of replication for fast proliferation and increased genomic instability. To overcome the consequences of improper replication control, malignant cells frequently inactivate parts of their DNA damage response (DDR) pathways (the ATM-CHK2-p53 pathway), while relying on other pathways which help to maintain replication fork stability (ATR-CHK1). This creates a dependency on the remaining DDR pathways, vulnerability to further destabilization of replication and synthetic lethality of DDR inhibitors with common oncogenic alterations such as mutations of TP53, RB1, ATM, amplifications of MYC, CCNE1 and others. The response to RS is normally limited by coordination of cell cycle, transcription and replication. Inhibition of WEE1 and PKMYT1 kinases, which prevent unscheduled mitosis entry, leads to fragility of under-replicated sites. Recent evidence also shows that inhibition of Cyclin-dependent kinases (CDKs), such as CDK4/6, CDK2, CDK8/19 and CDK12/13 can contribute to RS through disruption of DNA repair and replication control. Here, we review the main causes of RS in cancers as well as main therapeutic targets—ATR, CHK1, PARP and their inhibitors.

Key Proteins of Replication Stress Response and Cell Cycle Control as Cancer Therapy Targets

Cyclin-dependent kinase (CDK) sensors have facilitated investigations of the cell cycle in living cells. These genetically encoded fluorescent biosensors change their subcellular location upon activation of CDKs. Activation is primarily regulated by their association with cyclins, which in turn trigger cell-cycle progression. In the absence of CDK activity, cells exit the cell cycle and become quiescent, a key step in stem cell maintenance and cancer cell dormancy. The evolutionary conservation of CDKs has allowed for the rapid development of CDK activity sensors for cell lines and several research organisms, including nematodes, fish, and flies. CDK activity sensors are utilized for their ability to visualize the exact moment of cell-cycle commitment. This has provided a breakthrough in understanding the proliferation-quiescence decision. Further adoption of these biosensors will usher in new discoveries focused on the cell-cycle regulation of development, ageing, and cancer. 

CDK activity sensors: genetically encoded ratiometric biosensors for live analysis of the cell cycle

DDK promotes DNA replication initiation: Mechanistic and structural insights.

The entry of mammalian cells into the DNA synthesis phase (S phase) represents a key event in cell division1. According to current models of the cell cycle, the kinase CDC7 constitutes an essential and rate-limiting trigger of DNA replication, acting together with the cyclin-dependent kinase CDK2. Here we show that CDC7 is dispensable for cell division of many different cell types, as determined using chemical genetic systems that enable acute shutdown of CDC7 in cultured cells and in live mice. We demonstrate that another cell cycle kinase, CDK1, is also active during G1/S transition both in cycling cells and in cells exiting quiescence. We show that CDC7 and CDK1 perform functionally redundant roles during G1/S transition, and at least one of these kinases must be present to allow S-phase entry. These observations revise our understanding of cell cycle progression by demonstrating that CDK1 physiologically regulates two distinct transitions during cell division cycle, whereas CDC7 has a redundant function in DNA replication. In addition to CDC7, the cell cycle kinase CDK1 has a pivotal role in the G1/S transition of cells, a finding that revises our current understanding of cell cycle progression. 

CDC7-independent G1/S transition revealed by targeted protein degradation

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CDC7-independent G1/S transition revealed by targeted protein degradation