Chk1–cyclin A/Cdk1 axis regulates origin firing programs in mammals

Nakanishi, Makoto; Katsuno, Yuko; Niida, Hiroyuki; Murakami, Hiroshi; Shimada, Midori

doi:10.1007/s10577-009-9086-2

Cited by 21 publications

(15 citation statements)

References 59 publications

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“…In metazoan cells, origins are activated by cyclin-dependent kinases and cdc7 kinases, which phosphorylate the MCM2–7 activating the MCM helicases and inducing melting of double-stranded DNA at the origin of replication (23,50). Because MDM2 upregulates cyclin D2 and cyclin A expression in cells lacking WT p53, we considered whether an increase in expression of cyclins led to enhanced activation of cyclin-dependent kinases, and thus activation of origins, generating replication stress and intra-S-phase checkpoint signaling.…”

Section: Resultsmentioning

confidence: 99%

The human oncoprotein MDM2 induces replication stress eliciting early intra-S-phase checkpoint response and inhibition of DNA replication origin firing

Frum

Singh

Vaughan

et al. 2013

Nucleic Acids Research

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Conventional paradigm ascribes the cell proliferative function of the human oncoprotein mouse double minute2 (MDM2) primarily to its ability to degrade p53. Here we report that in the absence of p53, MDM2 induces replication stress eliciting an early S-phase checkpoint response to inhibit further firing of DNA replication origins. Partially synchronized lung cells cultured from p53−/−:MDM2 transgenic mice enter S phase and induce S-phase checkpoint response earlier than lung cells from p53−/− mice and inhibit firing of DNA replication origins. MDM2 activates chk1 phosphorylation, elevates mixed lineage lymphoma histone methyl transferase levels and promotes checkpoint-dependent tri-methylation of histone H3 at lysine 4, known to prevent firing of late replication origins at the early S phase. In the absence of p53, a condition that disables inhibition of cyclin A expression by MDM2, MDM2 increases expression of cyclin D2 and A and hastens S-phase entry of cells. Consistently, inhibition of cyclin-dependent kinases, known to activate DNA replication origins during firing, inhibits MDM2-mediated induction of chk1 phosphorylation indicating the requirement of this activity in MDM2-mediated chk1 phosphorylation. Our data reveal a novel pathway, defended by the intra-S-phase checkpoint, by which MDM2 induces unscheduled origin firing and accelerates S-phase entry of cells in the absence of p53.

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Section: Resultsmentioning

confidence: 99%

The human oncoprotein MDM2 induces replication stress eliciting early intra-S-phase checkpoint response and inhibition of DNA replication origin firing

Frum

Singh

Vaughan

et al. 2013

Nucleic Acids Research

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“…It is known that in mammalian cells, DNA replication origins are activated by cyclin-dependent kinases (CDK) and CDC7 kinase, which induces melting of double-stranded DNA at the origin of replication (44,45). Since GOF p53 induces origin firing, a CDC7 kinase inhibitor, PHA767491, which specifically prevents activation of origins but does not prevent fork progression (46,47), was used to determine whether inhibition of origin firing in lung cells harboring a GOF p53 mutation would reduce frequency of micronuclei formation.…”

Section: 4mentioning

confidence: 99%

Mutant p53 establishes targetable tumor dependency by promoting unscheduled replication

Singh¹,

Vaughan²,

Frum³

et al. 2017

Journal of Clinical Investigation

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“…They also point out that the different activation pathways for cdk1 and cdk2 contribute to the initation of cyclin A/cdk1 activity at the end of S phase. 52,53 In addition chk1 kinase acts to prevent premature activation of cyclin A/ cdk1, by destabilizing Cdc25A. 52,53 It is possible that cyclin A-bound cdk1 is either more readily dephosphorylated by Cdc25 and/or resistant to inhibitory phosphorylations by kinases such as Wee1.…”

Section: Acknowledgementsmentioning

confidence: 99%

“…52,53 In addition chk1 kinase acts to prevent premature activation of cyclin A/ cdk1, by destabilizing Cdc25A. 52,53 It is possible that cyclin A-bound cdk1 is either more readily dephosphorylated by Cdc25 and/or resistant to inhibitory phosphorylations by kinases such as Wee1. This may be the reason for detection of cyclin A/ cdk1 activity starting from late S phase toward G 2, where it peaks, while cyclin B/ cdk1 activity stays low until G 2 /M when a rapid activity increase causes M phase entry.…”

Section: Acknowledgementsmentioning

confidence: 99%

Coordinate regulation of histone mRNA metabolism and DNA replication

2010

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s phase is characterized by the replication of dna and assembly of chromatin. this requires the synthesis of large amounts of histone proteins to package the newly replicated dna. histone mrnas are the only mrnas that do not have polya tails, ending instead in a conserved stemloop sequence. the stemloop binding protein (slBP) that binds the 3' end of histone mrna is cell cycle regulated and slBP is required in all steps of histone mrna metabolism. activation of cyclin e/cdk2 prior to entry into s-phase is critical for initiation of dna replication and histone mrna accumulation. at the end of s phase slBP is rapidly degraded as a result of phosphorylation of slBP by cyclin a/cdk1 and cK2 effectively shutting off histone mrna biosynthesis. e2f1, which is required for expression of many s-phase genes, is regulated in parallel with slBP and its degradation also requires a cyclin binding site, suggesting that it may also be regulated by the same pathway. it is likely that activation of cyclin a/cdk1 helps inhibit both dna replication and histone mrna accumulation, marking the end of s phase and entry into G 2 -phase.Progression through the cell cycle is driven by sequential activation of a series of protein kinases, the cyclin/cdks. of cell growth pathways and then initiation of DNA replication. During S phase, cyclin A/cdk2 is essential for ongoing DNA replication. Prior to entry into mitosis, activation of cyclin B/cdk1 results in nuclear envelope breakdown. Completion of mitosis requires the inactivation of both mitotic cyclins, cyclin B/cdk1 and cyclin A/cdk1 by destruction of the cyclin subunits by the anaphase-promoting complex (APC). It is less clear whether there is a specific transition that occurs at the end of S phase and entry into G 2 -phase. Histone protein synthesis is restricted to S phase and regulation of histone protein synthesis is accomplished by regulation of histone mRNA levels. Replication histone mRNAs have a unique structure since they are the only eukaryotic mRNAs that are not polyadenylated, ending instead in a conserved stemloop. A novel RNA-binding protein, stemloop binding protein (SLBP), binds the 3' end of histone mRNA and participates in many aspects of histone mRNA metabolism.2 SLBP is cell cycle-regulated and the protein is rapidly degraded at the end of S phase. 3,4 In a recent study, we demonstrated that the degradation of SLBP, a protein that is limiting for histone mRNA accumulation, requires phosphorylation by cyclin A/cdk1 which in turn primes the phosphorylation of an adjacent threonine by casein kinase 2 (CK2).5 SLBP is subsequently degraded by a still-unknown ubiquitin ligase. The degradation of SLBP

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Chk1–cyclin A/Cdk1 axis regulates origin firing programs in mammals

Cited by 21 publications

References 59 publications

The human oncoprotein MDM2 induces replication stress eliciting early intra-S-phase checkpoint response and inhibition of DNA replication origin firing

The human oncoprotein MDM2 induces replication stress eliciting early intra-S-phase checkpoint response and inhibition of DNA replication origin firing

Mutant p53 establishes targetable tumor dependency by promoting unscheduled replication

Coordinate regulation of histone mRNA metabolism and DNA replication

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