Cyclin A–Cdk1 regulates the origin firing program in mammalian cells

Katsuno, Yuko; Suzuki, Ayumi; Sugimura, Kazuto; Okumura, Katsuhiko; Zineldeen, Doaa H.; Shimada, Midori; Niida, Hiroyuki; Mizuno, Takeshi; Hanaoka, Fumio; Nakanishi, Makoto

doi:10.1073/pnas.0809350106

Cited by 133 publications

(149 citation statements)

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“…We found that in normal MEFs, cyclin A2-Cdk1 activity first appeared at middle S phase and increased thereafter, whereas cyclin A2-Cdk2 activity was detected at early S phase (Katsuno et al 2009). These results are consistent with those of a recent study using centrifugal cell elutriation which showed that cyclin A assembles with Cdk1 only after complex formation with Cdk2 reaches a plateau during late S and G2 phases (Merrick et al 2008).…”

Section: Chk1 But Not Chk2 Is a Regulator Of The Origin Firing Programentioning

confidence: 97%

“…Consistent with this, Chk1 −/− somatic cells permanently arrest the cell cycle at middle S phase, preventing analysis of the S phase program in Chk1 −/− cells. Using the Cre/loxP system, we carefully synchronized Chk1 del/− MEFs at S phase onset and analyzed their spatiotemporal replication site patterns during early to middle S phase (Katsuno et al 2009). Double-labeling of cells with IdU and CIdU revealed that Chk1 depletion in mammals resulted in aberrant origin firing as observed in avian cells (Fig.…”

Section: Chk1 But Not Chk2 Is a Regulator Of The Origin Firing Programentioning

confidence: 99%

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

et al. 2009

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DNA replication is key to ensuring the complete duplication of genomic DNA prior to mitosis and is tightly regulated by both cell cycle machinery and checkpoint signals. Regulation of the S phase program occurs at several stages, affecting origin firing, replication fork elongation, fork velocity, and fork stability, all of which are dependent on S-phase-promoting kinase activity. Somatic mammalian cells use well-established origin programs by which specific regions of the genome are replicated at precise times. However, the mechanisms by which S phase kinases regulate origin firing in mammals are largely unknown. Here, we discuss recent advances in the understanding of how S phase programs are regulated in mammals at the correct regions and at the appropriate times.

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Section: Chk1 But Not Chk2 Is a Regulator Of The Origin Firing Programentioning

confidence: 97%

Section: Chk1 But Not Chk2 Is a Regulator Of The Origin Firing Programentioning

confidence: 99%

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

et al. 2009

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“…1 B and C). In addition, we identified BAZ1A/ACF1, required for DNA replication through heterochromatin (31); SetD8, for replication licensing (32); MYST2/HBO1, controlling MCM loading via ORC1 binding (33); and CCNA2-CDK1, regulating origin firing (34) (Fig. 1A).…”

Section: Identification Of New Lmo2 Protein-protein Interactions In Hmentioning

confidence: 99%

The LMO2 oncogene regulates DNA replication in hematopoietic cells

Sincennes

Humbert

Grondin

et al. 2016

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

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Oncogenic transcription factors are commonly activated in acute leukemias and subvert normal gene expression networks to reprogram hematopoietic progenitors into preleukemic stem cells, as exemplified by LIM-only 2 (LMO2) in T-cell acute lymphoblastic leukemia (T-ALL). Whether or not these oncoproteins interfere with other DNA-dependent processes is largely unexplored. Here, we show that LMO2 is recruited to DNA replication origins by interaction with three essential replication enzymes: DNA polymerase delta (POLD1), DNA primase (PRIM1), and minichromosome 6 (MCM6). Furthermore, tethering LMO2 to synthetic DNA sequences is sufficient to transform these sequences into origins of replication. We next addressed the importance of LMO2 in erythroid and thymocyte development, two lineages in which cell cycle and differentiation are tightly coordinated. Lowering LMO2 levels in erythroid progenitors delays G1-S progression and arrests erythropoietin-dependent cell growth while favoring terminal differentiation. Conversely, ectopic expression in thymocytes induces DNA replication and drives these cells into cell cycle, causing differentiation blockade. Our results define a novel role for LMO2 in directly promoting DNA synthesis and G1-S progression.M ore than 70% of recurring chromosomal translocations in T-cell acute lymphoblastic leukemia (T-ALL) involve transcription factors that are master regulators of cell fate. These oncogenic transcription factors determine the gene signature and leukemic cell types (1). Whether these DNA-bound factors may have additional roles beyond modulating gene expression remains unknown. LMO2, a 17-kDa protein defined by tandem zinc finger domains, is an essential nucleation factor that assembles a multipartite transcriptional regulatory complex on gene regulatory regions via direct interaction with the TAL1/SCL transcription factor, LDB1, and other DNA binding transcription factors (2-4, reviewed in refs. 5, 6). These complexes drive gene expression programs that determine hematopoietic cell fates at critical branchpoints both during embryonic development (7) and in adult hematopoietic stem cells (8, 9). Lmo2 function is essential in highly proliferative erythroid progenitors (10, reviewed in refs. 5, 6). Interestingly, Lmo2 down-regulation is required for terminal erythroid differentiation (11,12). Because commitment to terminal differentiation is coordinated with growth arrest (13), Lmo2 may have additional molecular functions that impede this critical step marked by growth cessation.In mouse models of T-ALL, LMO1 or LMO2 collaborates with SCL to inhibit the activity of two basic helix-loop-helix (bHLH) transcription factors that control thymocyte differentiation, E2A/ TCF3 and HEB/TCF12, causing differentiation arrest (reviewed in ref. 14). However, this inhibition is not sufficient, per se, for leukemogenesis, because both TAL1 and LYL1 inhibit E proteins but require interaction with LMO1/2 to activate the transcription of a self-renewal gene network in thymocytes (15,16) and to induc...

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“…The synchronous activation of contiguous replicons within clusters emphasizes the importance of coordination during synthesis, and although the regulatory mechanisms are unknown, these observations are at least consistent with a role for some form of a factory level control process. As the S phase proceeds, changes in expression of different cyclin-CDK complexes serve to increase the potency of potential origins in heterochromatin at late times of the S phase (Katsuno et al 2009). Hence, the combination of accessibility of potential origins in open chromatin during early S phase, subsequent increase in activity of remaining potential origins in late S phase and robust checkpoints for DNA completion ensures that synthesis is performed in a way that defines the preservation of both genetic and epigenetic information.…”

Section: S-phase Progressionmentioning

confidence: 99%

Spatio-Temporal Organization of Replication in Bacteria and Eukaryotes (Nucleoids and Nuclei)

Jackson

Wang²,

Rudner³

2012

Cold Spring Harbor Perspectives in Biology

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Here we discuss the spatio-temporal organization of replication in eubacteria and eukaryotes. Although there are significant differences in how replication is organized in cells that contain nuclei from those that do not, you will see that organization of replication in all organisms is principally dictated by the structured arrangement of the chromosome. We will begin with how replication is organized in eubacteria with particular emphasis on three well studied model organisms. We will then discuss spatial and temporal organization of replication in eukaryotes highlighting the similarities and differences between these two domains of life.

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Cyclin A–Cdk1 regulates the origin firing program in mammalian cells

Cited by 133 publications

References 31 publications

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

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

The LMO2 oncogene regulates DNA replication in hematopoietic cells

Spatio-Temporal Organization of Replication in Bacteria and Eukaryotes (Nucleoids and Nuclei)

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