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Mec1 is activated at the onset of normal S phase by low dNTP pools impeding DNA replication

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

ORGANISM(S): Saccharomyces cerevisiae

PROVIDER: GSE136605 | GEO | 2020/03/17

REPOSITORIES: GEO

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Mec1 is activated at the onset of normal S phase by low dNTP pools impeding DNA replication [microarray]

Project description:The Mec1 and Rad53 kinases play a central role during acute replication stress in budding yeast. They are also essential for viability in normal growth conditions, but the signal that activates the Mec1–Rad53 pathway in the absence of exogenous insults is currently unknown. Here, we show that this pathway is active at the onset of normal S phase because dNTP levels present in G1 phase are not sufficient to support processive DNA synthesis and impede DNA replication. This activation can be suppressed experimentally by increasing dNTP levels in G1 phase. Moreover, we show that unchallenged cells entering S phase in the absence of Rad53 undergo irreversible fork collapse and mitotic catastrophe. Together, these data indicate that cells use dNTP shortage to detect the onset of DNA replication and activate the Mec1–Rad53 pathway, which in turn maintains functional forks and triggers dNTP synthesis, allowing the completion of DNA replication.

2020-03-17 | GSE136601 | GEO

Mec1 is activated at the onset of normal S phase by low dNTP pools impeding DNA replication [sequencing]

2020-03-17 | GSE136602 | GEO

Mec1 is activated at the onset of normal S phase by low dNTP pools impeding DNA replication

Project description:Mec1 is activated at the onset of normal S phase by low dNTP pools impeding DNA replication

| PRJNA562848 | ENA

Mec1 is activated at the onset of normal S phase by low dNTP pools impeding DNA replication [sequencing]

Project description:Mec1 is activated at the onset of normal S phase by low dNTP pools impeding DNA replication [sequencing]

| PRJNA562847 | ENA

Mec1 is activated at the onset of normal S phase by low dNTP pools impeding DNA replication [microarray]

Project description:Mec1 is activated at the onset of normal S phase by low dNTP pools impeding DNA replication [microarray]

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Chl1 helicase controls replication fork progression by regulating dNTP pools.

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dNTP pools determine fork progression and origin usage under replication stress.

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dNTP pools determine fork progression and origin usage under replication stress

Project description:Intracellular levels of deoxyribonucleoside triphosphate (dNTP) must be tightly regulated to preserve genome integrity. Indeed, alterations in dNTP pools have recently been associated with increased mutagenesis, genomic instability and tumorigenesis. However, the mechanisms by which low or imbalanced dNTP pools affect DNA replication remain poorly understood. Here, we have modulated the activity of ribonucleotide reductase (RNR), a key enzyme catalyzing a rate-limiting step of dNTP production, to monitor the effect of altered dNTP levels on replication dynamics in budding yeast. We show that dNTP pools are limiting for normal DNA synthesis as upregulation of RNR activity increases replication fork speed. In contrast, inhibition of RNR activity with hydroxyurea (HU) induces a sharp transition from a regular- to a slow-replication mode within minutes after S-phase entry. Interestingly, we found that upregulation of RNR activity delays this transition and that dNTP levels modulate both fork speed and origin usage under replication stress. Moreover, we report that chromosomal instability (CIN) mutants show increased dNTP pools and enhanced DNA synthesis in the presence of HU. Since upregulation of RNR allows forks to progress faster in the presence of DNA lesions, we propose that CIN mutants adapt to chronic replication stress by upregulating dNTP pools.

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