Non-transcriptional control of DNA replication by c-Myc

Dominguez-Sola, David; Ying, Carol Y.; Grandori, Carla; Ruggiero, Luca; Chen, Brenden; Li, Muyang; Galloway, Denise A.; Gu, Wei; Gautier, Jean; Dalla‐Favera, Riccardo

doi:10.1038/nature05953

Cited by 585 publications

(589 citation statements)

References 49 publications

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“…The molecular mechanism(s), however, by which transcription factors increase origin selectivity are still largely unknown (34). Transcription factors can also play crucial roles in origin activation, such as the c-Myc proto-oncogene, whose overexpression causes an increase in the number of active replicons (15). Since the origins examined in our study were all bound by pre-RC factors in the cells analyzed, independently of exogenous HOXD13 gene expression (see Fig.…”

Section: Discussionmentioning

confidence: 99%

HOXD13 Binds DNA Replication Origins To Promote Origin Licensing and Is Inhibited by Geminin

Salsi¹,

Ferrari²,

Ferraresi

et al. 2009

Molecular and Cellular Biology

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HOX DNA-binding proteins control patterning during development by regulating processes such as cell aggregation and proliferation. Recently, a possible involvement of HOX proteins in replication origin activity was suggested by results showing that a number of HOX proteins interact with the DNA replication licensing regulator geminin and bind a characterized human origin of replication. The functional significance of these observations, however, remained unclear. We show that HOXD13, HOXD11, and HOXA13 bind in vivo all characterized human replication origins tested. We furthermore show that HOXD13 interacts with the CDC6 loading factor, promotes pre-replication complex (pre-RC) proteins assembly at origins, and stimulates DNA synthesis in an in vivo replication assay. HOXD13 expression in cultured cells accelerates DNA synthesis initiation in correlation with the earlier pre-RC recruitment onto origins during G 1 phase. Geminin, which interacts with HOXD13 as well, blocks HOXD13-mediated assembly of pre-RC proteins and inhibits HOXD13-induced DNA replication. Our results uncover a function for Hox proteins in the regulation of replication origin activity and reveal an unforeseen role for the inhibition of HOX protein activity by geminin in the context of replication origin licensing.Hox proteins belong to the large family of homeodomaincontaining DNA-binding proteins. During embryonic development they control cell fates, eventually leading to the generation of different regional identities along the primary body and limb axes (17,35). Genetic analyses, including loss-and gainof-function experiments, showed that vertebrate Hox genes modulate morphogenetic processes by controlling crucial aspects such as cell proliferation and aggregation (16). This is particularly true of 5Ј HoxA and HoxD genes, which are involved in limb patterning (reviewed in references 49 and 65). The inactivation of the Hoxd13 gene in mice, for instance, causes a phenotype resulting from defects in the proliferation and/or condensation of limb mesenchymal cells (11,14).Hox proteins have been shown to act as transcription factors, which are thought to regulate sets of target genes by binding to specific DNA sequences within the transcriptional regulatory regions of these (7,33,38,43,50,51,61,62). Recent findings, however, have hinted at a possible additional function for this family of DNA-binding proteins. Hox proteins have been found to associate with the DNA replication licensing regulator geminin (39), and a number of them have been shown to bind the human LaminB2 and other origins of replication, suggesting their possible role in origin definition and/or assembly of the replication machinery (9,13,20). The functional significance of these observations, however, remained elusive.Origins of replication are poorly defined in metazoa. A consensus sequence appears not to be required for replication initiation in human cells, and only a few origins where replication initiates from a localized site in each cell cycle have been well characterize...

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Section: Discussionmentioning

confidence: 99%

HOXD13 Binds DNA Replication Origins To Promote Origin Licensing and Is Inhibited by Geminin

Salsi¹,

Ferrari²,

Ferraresi

et al. 2009

Molecular and Cellular Biology

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“…Cdt1 has been shown to physically interact with Cdc6 in several organisms. In addition, a recent paper reported that human Orc6 co-immunoprecipitates with Cdt1 (34). In theory, geminin could disrupt either of these interactions (35).…”

Section: Discussionmentioning

confidence: 99%

Human Cdt1 Lacking the Evolutionarily Conserved Region That Interacts with MCM2–7 Is Capable of Inducing Re-replication

Teer

Dutta

2008

Journal of Biological Chemistry

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Replication initiation must be a carefully regulated process to avoid genomic instability caused by aberrant replication. In eukaryotic cells, distinct steps of protein loading (origin licensing) and replication activation are choreographed such that a cell can replicate only once per cell cycle. The first proteins recruited to the origins form the pre-replication complex. Of these proteins, Cdt1 is of interest, as it is the focus of several pathways to control replication initiation. It is degraded by two different pathways, mediated by the interaction of Cdt1 with proliferating cell nuclear antigen (PCNA) or with cyclin-Cdk2 and inhibited by geminin once cells are in S-phase, presumably to prevent reloading of pre-replication complexes once S-phase has begun. Although the requirement of Cdt1 in loading MCM2-7 is known, the mechanism by which overexpressed Cdt1 stimulates re-replication is unclear. In this study we have designed various mutations in Cdt1 to determine which portion of Cdt1 is important for re-replication, providing insight into possible mechanisms. Surprisingly, we found that mutants of Cdt1 that do not interact with MCM2-7 are able to induce rereplication when overexpressed. The re-replication is not due to titration of geminin from endogenous Cdt1 and is not accompanied by stabilization of endogenous Cdt1. Additionally, the N-terminal one-third of Cdt1 is sufficient to induce re-replication. The N terminus contains the PCNA-and cyclin-interacting motifs, and deletion of both motifs simultaneously in the overexpressed Cdt1 prevents re-replication. These findings suggest that exogenous Cdt1 induces re-replication by de-repressing endogenous Cdt1 through the titration of PCNA and cyclin.

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“…However, most of its targets are only moderately affected by Myc (reviewed by Dang et al, 2006). In addition, Myc has transcription-independent roles in the control of DNA replication (Dominguez-Sola et al, 2007).…”

Section: Introductionmentioning

confidence: 99%

The conserved Myc box 2 and Myc box 3 regions are important, but not essential, for Myc function in vivo

Schwinkendorf¹,

Gallant²

2009

Gene

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Non-transcriptional control of DNA replication by c-Myc

Cited by 585 publications

References 49 publications

HOXD13 Binds DNA Replication Origins To Promote Origin Licensing and Is Inhibited by Geminin

HOXD13 Binds DNA Replication Origins To Promote Origin Licensing and Is Inhibited by Geminin

Human Cdt1 Lacking the Evolutionarily Conserved Region That Interacts with MCM2–7 Is Capable of Inducing Re-replication

The conserved Myc box 2 and Myc box 3 regions are important, but not essential, for Myc function in vivo

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