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

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Mus musculus

PROVIDER: GSE212196 | GEO | 2022/12/31

REPOSITORIES: GEO

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

Project description: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 in early S phase, but by mid-S phase they display dNTP depletion, fork stalling, and replication failure. Nonetheless, productive DNA replication can be restored in Atr-deficient cells by pathways that suppress origin firing, such as downregulation 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 other replication factors.

2022-12-31 | GSE212195 | GEO

ATR kinase supports normal proliferation in the early S phase by preventing replication resource exhaustion [RNA-seq]

2022-12-31 | GSE212194 | GEO

ATR kinase supports normal proliferation in the early S phase by preventing replication resource exhaustion [CRISPR-Cas9 gRNA screen]

2022-12-31 | GSE214643 | GEO

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

Project description:ATR kinase supports normal proliferation in the early S phase by preventing replication resource exhaustion.

| PRJNA874443 | ENA

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

Project description:ATR kinase supports normal proliferation in the early S phase by preventing replication resource exhaustion [HTGTS]

| PRJNA874445 | ENA

ATR kinase supports normal proliferation in the early S phase by preventing replication resource exhaustion [RNA-seq]

Project description:ATR kinase supports normal proliferation in the early S phase by preventing replication resource exhaustion [RNA-seq]

| PRJNA874444 | ENA

ATR kinase supports normal proliferation in the early S phase by preventing replication resource exhaustion [CRISPR-Cas9 gRNA screen]

Project description:ATR kinase supports normal proliferation in the early S phase by preventing replication resource exhaustion [CRISPR-Cas9 gRNA screen]

| PRJNA886447 | ENA

ATR-like kinase Mec1 facilitates both chromatin accessibility at DNA replication forks and replication fork progression during replication stress.

Project description:Faithful DNA replication is essential for normal cell division and differentiation. In eukaryotic cells, DNA replication takes place on chromatin. This poses the critical question as to how DNA replication can progress through chromatin, which is inhibitory to all DNA-dependent processes. Here, we developed a novel genome-wide method to measure chromatin accessibility to micrococcal nuclease (MNase) that is normalized for nucleosome density, the NCAM (normalized chromatin accessibility to MNase) assay. This method enabled us to discover that chromatin accessibility increases specifically at and ahead of DNA replication forks in normal S phase and during replication stress. We further found that Mec1, a key regulatory ATR-like kinase in the S-phase checkpoint, is required for both normal chromatin accessibility around replication forks and replication fork rate during replication stress, revealing novel functions for the kinase in replication stress response. These results suggest a possibility that Mec1 may facilitate DNA replication fork progression during replication stress by increasing chromatin accessibility around replication forks.

| S-EPMC3553285 | biostudies-literature

The ATR-WEE1 kinase module inhibits the MAC complex to regulate replication stress response.

Project description:DNA damage response is a fundamental mechanism to maintain genome stability. The ATR-WEE1 kinase module plays a central role in response to replication stress. Although the ATR-WEE1 pathway has been well studied in yeasts and animals, how ATR-WEE1 functions in plants remains unclear. Through a genetic screen for suppressors of the Arabidopsis atr mutant, we found that loss of function of PRL1, a core subunit of the evolutionarily conserved MAC complex involved in alternative splicing, suppresses the hypersensitivity of atr and wee1 to replication stress. Biochemical studies revealed that WEE1 directly interacts with and phosphorylates PRL1 at Serine 145, which promotes PRL1 ubiquitination and subsequent degradation. In line with the genetic and biochemical data, replication stress induces intron retention of cell cycle genes including CYCD1;1 and CYCD3;1, which is abolished in wee1 but restored in wee1 prl1. Remarkably, co-expressing the coding sequences of CYCD1;1 and CYCD3;1 partially restores the root length and HU response in wee1 prl1. These data suggested that the ATR-WEE1 module inhibits the MAC complex to regulate replication stress responses. Our study discovered PRL1 or the MAC complex as a key downstream regulator of the ATR-WEE1 module and revealed a novel cell cycle control mechanism.

| S-EPMC7897505 | biostudies-literature

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

Project description: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.

| S-EPMC6613105 | biostudies-literature

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