A novel checkpoint mechanism regulating the G1/S transition

Tvegård, Tonje; Soltani, Héla; Skjølberg, Henriette C.; Krohn, Marit; Nilssen, Esben A.; Kearsey, Stephen; Grallert, Beáta; Boye, Erik

doi:10.1101/gad.421807

Cited by 53 publications

(83 citation statements)

References 32 publications

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“…1 C and D). These data show, as seen before (10), that the cells delay S-phase entry for more than 30 min in response to UVC irradiation and that the three parameters give consistent reports on cell-cycle progression. The phosphorylation of eIF2α was monitored as a measure of Gcn2 activation and it coincided with the length of the cell-cycle delay (Fig.…”

Section: Resultssupporting

confidence: 65%

“…We have shown that fission yeast cells delay entry into S phase after UVC irradiation by a Gcn2-dependent mechanism (10). Here, we demonstrate that this radiation-induced delay in G 1 phase depends on processing of the DNA damage.…”

Section: Discussionmentioning

confidence: 72%

“…7). Furthermore, activation of Gcn2 is not sufficient to produce a G 1 delay, although Gcn2 is absolutely required for the checkpoint both in wild-type cells (10) and in repair-deficient cells (Fig. 6).…”

Section: Discussionmentioning

confidence: 99%

“…The delay was determined as the time difference at reaching maximal preRC loading between irradiated and unirradiated cells. We have published that gcn2 cells have no UVC-induced delay (10), and a summary of these previously published data are shown here for comparison.…”

Section: Deletion Of Gcn2 Reduces But Does Not Abolish the Prolonged Gmentioning

confidence: 99%

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Induction of a G ₁ -S checkpoint in fission yeast

Bøe

Krohn

Rødland

et al. 2012

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

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Entry into S phase is carefully regulated and, in most organisms, under the control of a G 1 -S checkpoint. We have previously described a G 1 -S checkpoint in fission yeast that delays formation of the prereplicative complex at chromosomal replication origins after exposure to UV light (UVC). This checkpoint absolutely depends on the Gcn2 kinase. Here, we explore the signal for activation of the Gcn2-dependent G 1 -S checkpoint in fission yeast. If some form of DNA damage can activate the checkpoint, deficient DNA repair should affect the length of the checkpoint-induced delay. We find that the cell-cycle delay differs in repair-deficient mutants from that in wild-type cells. However, the duration of the delay depends not only on the repair capacity of the cells, but also on the nature of the repair deficiency. First, the delay is abolished in cells that are deficient in the early steps of repair. Second, the delay is prolonged in repair mutants that fail to complete repair after the incision stage. We conclude that the G 1 -S delay depends on damage to the DNA and that the activating signal derives not from the initial DNA damage, but from a repair intermediate(s). Surprisingly, we find that activation of Gcn2 does not depend on the processing of DNA damage and that activated Gcn2 alone is not sufficient to delay entry into S phase in UVC-irradiated cells. Thus, the G 1 -S delay depends on at least two different inputs.

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Section: Resultssupporting

confidence: 65%

Section: Discussionmentioning

confidence: 72%

Section: Discussionmentioning

confidence: 99%

Section: Deletion Of Gcn2 Reduces But Does Not Abolish the Prolonged Gmentioning

confidence: 99%

See 2 more Smart Citations

Induction of a G ₁ -S checkpoint in fission yeast

Bøe

Krohn

Rødland

et al. 2012

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

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“…Control of pre-replication complex stability has previously been suggested as a critical component in regulation of S-phase initiation during SAM-limitation in budding yeast 19 and in response to UV-irradiation in fission yeast. 33 Pre-replication complex assembly might thus represent an underappreciated cell cycle checkpoint target that could be particularly important to link cell proliferation with cellular metabolites. Our results suggest that SAM is the critical mediator of cancer cell methionine dependency, and it is tempting to speculate that the pathway we describe represents a cell cycle checkpoint that ensures epigenetic stability by preventing S-phase during limited SAM availability.…”

Section: Discussionmentioning

confidence: 99%

Downregulation of Cdc6 and pre-replication complexes in response to methionine stress in breast cancer cells

et al. 2012

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New functions of protein kinase Gcn2 in yeast and mammals

Murguía

Serrano

2012

IUBMB Life

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SummaryThe classical role of the conserved Gcn2 kinase of yeast and mammals is to activate the translation of the transcription factors Gcn4 in yeast and activating transcription factor 4 in mammals by phosphorylating the eukaryotic translation initiation factor 2a. Gcn2 is activated by uncharged tRNAs in response to amino acid starvation and this regulatory system is important for tolerance to nutrient deprivation and other stresses and for development, differentiation, and normal function of mammalian organs. In the past few years, the classical Gcn2 pathway has been shown to modulate life span, tumor cell survival, and immune responses. In addition, Gcn2 modulates translation of novel mRNAs such as those of an unknown regulator of leucine transport and of sulfiredoxin SRX1 in yeast (activation of translation) and of inducible nitric oxide synthase, ErBb2, HIF1a, and 5 0 -terminal oligopyrimidine tract mRNAs in mammals (inhibition of translation). Finally, Gcn2 directly phosphorylates novel proteins such as methionyl-tRNA synthetase in mammals, and this triggers a pathway for DNA repair. These findings anticipate many expanding roles of Gcn2 in the future, with relevance for stress responses and human disease.2012 IUBMB IUBMB Life, 64(12): 971-974, 2012

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A novel checkpoint mechanism regulating the G1/S transition

Cited by 53 publications

References 32 publications

Induction of a G ₁ -S checkpoint in fission yeast

Induction of a G ₁ -S checkpoint in fission yeast

Downregulation of Cdc6 and pre-replication complexes in response to methionine stress in breast cancer cells

New functions of protein kinase Gcn2 in yeast and mammals

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A novel checkpoint mechanism regulating the G1/S transition

Cited by 53 publications

References 32 publications

Induction of a G 1 -S checkpoint in fission yeast

Induction of a G 1 -S checkpoint in fission yeast

Downregulation of Cdc6 and pre-replication complexes in response to methionine stress in breast cancer cells

New functions of protein kinase Gcn2 in yeast and mammals

Contact Info

Product

Resources

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Induction of a G ₁ -S checkpoint in fission yeast

Induction of a G ₁ -S checkpoint in fission yeast