Mec1/ATR, the Program Manager of Nucleic Acids Inc.

Feng, Wenyi

doi:10.3390/genes8010010

Cited by 6 publications

(5 citation statements)

References 99 publications

(120 reference statements)

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“…In separate experiments, we found that combining the tub2 -430∆ with the DNA repair mutants mec1 ∆ and sml1 ∆ produces an additive increase in the frequency of cells with Rad52 foci (Supplemental Figure S2B). Cells containing the mec1 ∆ sml1 ∆ null mutations contain more DNA damage in S and G2 due to collapsed replication forks and proceed through anaphase without delay even when containing DNA damage (Lisby et al , 2001; Weinert, 1998; Feng, 2017).…”

Section: Resultsmentioning

confidence: 99%

Astral microtubule forces alter nuclear organization and inhibit DNA repair in budding yeast

Estrem

Moore

2019

MBoC

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Dividing cells must balance the maintenance of genome integrity with the generation of cytoskeletal forces that control chromosome position. In this study, we investigate how forces on astral microtubules impact the genome during cell division by using live-cell imaging of the cytoskeleton, chromatin, and DNA damage repair in budding yeast. Our results demonstrate that dynein-dependent forces on astral microtubules are propagated through the spindle during nuclear migration and when in excess can increase the frequency of double-stranded breaks (DSBs). Under these conditions, we find that homology-directed repair of DSBs is delayed, indicating antagonism between nuclear migration and the mechanism of homology-directed repair. These effects are partially rescued by mutants that weaken pericentric cohesion or mutants that decrease constriction on the nucleus as it moves through the bud neck. We propose that minimizing nuclear movement aids in finding a donor strand for homologous recombination.

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Section: Resultsmentioning

confidence: 99%

Astral microtubule forces alter nuclear organization and inhibit DNA repair in budding yeast

Estrem

Moore

2019

MBoC

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“…The main kinases of the cascade, Mec1 ATR and Rad53 CHK2 , are activated in response to aberrations in DNA replication [6–10]. Among all the various downstream effects, the essential role of Mec1-Rad53 has been demonstrated to be in regulation of the RNR activity in Saccharomyces cerevisiae [3, 11, 12].…”

Section: Introductionmentioning

confidence: 99%

Mck1 defines a key S-phase checkpoint effector in response to various degrees of replication threats

Jin

Sharma

et al. 2019

PLoS Genet

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The S-phase checkpoint plays an essential role in regulation of the ribonucleotide reductase (RNR) activity to maintain the dNTP pools. How eukaryotic cells respond appropriately to different levels of replication threats remains elusive. Here, we have identified that a conserved GSK-3 kinase Mck1 cooperates with Dun1 in regulating this process. Deleting MCK1 sensitizes dun1 Δ to hydroxyurea (HU) reminiscent of mec1 Δ or rad53 Δ. While Mck1 is downstream of Rad53, it does not participate in the post-translational regulation of RNR as Dun1 does. Mck1 phosphorylates and releases the Crt1 repressor from the promoters of DNA damage-inducible genes as RNR2-4 and HUG1 . Hug1, an Rnr2 inhibitor normally silenced, is induced as a counterweight to excessive RNR. When cells suffer a more severe threat, Mck1 inhibits HUG1 transcription. Consistently, only a combined deletion of HUG1 and CRT1 , confers a dramatic boost of dNTP levels and the survival of mck1 Δ dun1 Δ or mec1 Δ cells assaulted by a lethal dose of HU. These findings reveal the division-of-labor between Mck1 and Dun1 at the S-phase checkpoint pathway to fine-tune dNTP homeostasis.

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“…Stalled replication forks can also be broken down if not resolved, resulting in genomic instability and carcinogenesis [132,133]. To solve this issue, eukaryotes have evolved the MEC1/ATR pathway to combat the breakdown of the replication forks [134]. In addition, a stalled replication fork is protected by checkpoint and homologous recombination (HR) proteins [135].…”

Section: Cellular Responses To the Genome Stress From Dna Replicatmentioning

confidence: 99%

Replication Stress and Consequential Instability of the Genome and Epigenome

2019

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Cells must faithfully duplicate their DNA in the genome to pass their genetic information to the daughter cells. To maintain genomic stability and integrity, double-strand DNA has to be replicated in a strictly regulated manner, ensuring the accuracy of its copy number, integrity and epigenetic modifications. However, DNA is constantly under the attack of DNA damage, among which oxidative DNA damage is the one that most frequently occurs, and can alter the accuracy of DNA replication, integrity and epigenetic features, resulting in DNA replication stress and subsequent genome and epigenome instability. In this review, we summarize DNA damage-induced replication stress, the formation of DNA secondary structures, peculiar epigenetic modifications and cellular responses to the stress and their impact on the instability of the genome and epigenome mainly in eukaryotic cells.

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Mec1/ATR, the Program Manager of Nucleic Acids Inc.

Cited by 6 publications

References 99 publications

Astral microtubule forces alter nuclear organization and inhibit DNA repair in budding yeast

Astral microtubule forces alter nuclear organization and inhibit DNA repair in budding yeast

Mck1 defines a key S-phase checkpoint effector in response to various degrees of replication threats

Replication Stress and Consequential Instability of the Genome and Epigenome

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