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MTBP-Cellular Roles Underlying Cancer Formation and Disease
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MTBP-Cellular Roles Underlying Cancer Formation and Disease

A special issue of Biology (ISSN 2079-7737).

Deadline for manuscript submissions: closed (30 April 2022) | Viewed by 13867

Special Issue Editor

Dr. Dominik Boos

E-Mail Website
Guest Editor
Fakultät für Biologie, Universität Duisburg-Essen, 45117 Essen, Germany
Interests: vertebrate genome replication; replication origin firing, origin firing regulation, replication stress; MTBP; treslin

Special Issue Information

Dear Colleagues,

A gap needs to be bridged between two lines of research of the MTBP protein: whilst cell biological investigations implicated MTBP in diverse cellular processes, clinically-oriented work revealed connections between MTBP and cancer formation. How these biological and clinical MTBP roles are linked remains unknown.

MTBP was identified as an interactor and activator of Mdm2. Later, Mdm2-independent roles in cancer formation, the mitotic spindle assembly checkpoint, the control of the actin cytoskeleton and an involvement in Myc-dependent transcription were described. These findings raised the possibility that cellular processes like the control of p53 activity, chromosome segregation, cell migration, and the biology of the Myc oncogene may underlie MTBP’s role in cancer formation. Recently, MTBP was shown to be essential for the initiation of DNA replication, suggesting that replication and replication stress-related processes may underlie MTBP’s link to tumorigenesis. MTBP is the vertebrate orthologue of the Sld7 protein which is a core factor of replication initiation. Because mutations in replication initiation factors are connected to Meier–Gorlin syndrome, one might speculate about an implication of MTBP in this disease.

For this Special Issue we encourage submission of research and review manuscripts addressing the cell biological and biochemical functions of MTBP and Sld7 as well as the roles of MTBP in cancer and disease.

Dr. Dominik Boos
Guest Editor

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Keywords

  • MTBP protein
  • Sld7 protein 
  • cell biology
  • faithful genome replication and segregation 
  • cancer
  • Meier-Gorlin syndrome

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Published Papers (4 papers)

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Review

10 pages, 2450 KiB  
Review
Dimerization of Firing Factors for Replication Origin Activation in Eukaryotes: A Crucial Process for Simultaneous Assembly of Bidirectional Replication Forks?
by Seiji Tanaka and Shiho Ogawa
Biology 2022, 11(6), 928; https://doi.org/10.3390/biology11060928 - 17 Jun 2022
Cited by 3 | Viewed by 3198
Abstract
Controlling the activity of the heterohexameric Mcm2–7 replicative helicase is crucial for regulation of replication origin activity in eukaryotes. Because bidirectional replication forks are generated from every replication origin, when origins are licensed for replication in the first step of DNA replication, two [...] Read more.
Controlling the activity of the heterohexameric Mcm2–7 replicative helicase is crucial for regulation of replication origin activity in eukaryotes. Because bidirectional replication forks are generated from every replication origin, when origins are licensed for replication in the first step of DNA replication, two inactive Mcm2–7 heterohexiameric complexes are loaded around double stranded DNA as a head-to-head double hexamer. The helicases are subsequently activated via a ‘firing’ reaction, in which the Mcm2–7 double hexamer is converted into two active helicase units, the CMG complex, by firing factors. Dimerization of firing factors may contribute to this process by allowing simultaneous activation of two sets of helicases and thus efficient assembly of bidirectional replication forks. An example of this is dimerization of the firing factor Sld3/Treslin/Ticrr via its binding partner, Sld7/MTBP. In organisms in which no Sld7 ortholog has been identified, such as the fission yeast Schizosaccharomyces pombe, Sld3 itself has a dimerization domain, and it has been suggested that this self-interaction is crucial for the firing reaction in this organism. Dimerization induces a conformational change in Sdl3 that appears to be critical for the firing reaction. Moreover, Mcm10 also seems to be regulated by self-interaction in yeasts. Although it is not yet clear to what extent dimerization of firing factors contributes to the firing reaction in eukaryotes, we discuss the possible roles of firing factor dimerization in simultaneous helicase activation. Full article
(This article belongs to the Special Issue MTBP-Cellular Roles Underlying Cancer Formation and Disease)
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17 pages, 656 KiB  
Review
MTBP and MYC: A Dynamic Duo in Proliferation, Cancer, and Aging
by Brian C. Grieb and Christine M. Eischen
Biology 2022, 11(6), 881; https://doi.org/10.3390/biology11060881 - 8 Jun 2022
Cited by 12 | Viewed by 3188
Abstract
The oncogenic transcription factor c-MYC (MYC) is highly conserved across species and is frequently overexpressed or dysregulated in human cancers. MYC regulates a wide range of critical cellular and oncogenic activities including proliferation, metabolism, metastasis, apoptosis, and differentiation by transcriptionally activating or repressing [...] Read more.
The oncogenic transcription factor c-MYC (MYC) is highly conserved across species and is frequently overexpressed or dysregulated in human cancers. MYC regulates a wide range of critical cellular and oncogenic activities including proliferation, metabolism, metastasis, apoptosis, and differentiation by transcriptionally activating or repressing the expression of a large number of genes. This activity of MYC is not carried out in isolation, instead relying on its association with a myriad of protein cofactors. We determined that MDM Two Binding Protein (MTBP) indirectly binds MYC and is a novel MYC transcriptional cofactor. MTBP promotes MYC-mediated transcriptional activity, proliferation, and cellular transformation by binding in a protein complex with MYC at MYC-bound promoters. This discovery provided critical context for data linking MTBP to aging as well as a rapidly expanding body of evidence demonstrating MTBP is overexpressed in many human malignancies, is often linked to poor patient outcomes, and is necessary for cancer cell survival. As such, MTBP represents a novel and potentially broad reaching oncologic drug target, particularly when MYC is dysregulated. Here we have reviewed the discovery of MTBP and the initial controversy with its function as well as its associations with proliferation, MYC, DNA replication, aging, and human cancer. Full article
(This article belongs to the Special Issue MTBP-Cellular Roles Underlying Cancer Formation and Disease)
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19 pages, 1672 KiB  
Review
DDK: The Outsourced Kinase of Chromosome Maintenance
by Peter J. Gillespie and J. Julian Blow
Biology 2022, 11(6), 877; https://doi.org/10.3390/biology11060877 - 7 Jun 2022
Cited by 9 | Viewed by 3760
Abstract
The maintenance of genomic stability during the mitotic cell-cycle not only demands that the DNA is duplicated and repaired with high fidelity, but that following DNA replication the chromatin composition is perpetuated and that the duplicated chromatids remain tethered until their anaphase segregation. [...] Read more.
The maintenance of genomic stability during the mitotic cell-cycle not only demands that the DNA is duplicated and repaired with high fidelity, but that following DNA replication the chromatin composition is perpetuated and that the duplicated chromatids remain tethered until their anaphase segregation. The coordination of these processes during S phase is achieved by both cyclin-dependent kinase, CDK, and Dbf4-dependent kinase, DDK. CDK orchestrates the activation of DDK at the G1-to-S transition, acting as the ‘global’ regulator of S phase and cell-cycle progression, whilst ‘local’ control of the initiation of DNA replication and repair and their coordination with the re-formation of local chromatin environments and the establishment of chromatid cohesion are delegated to DDK. Here, we discuss the regulation and the multiple roles of DDK in ensuring chromosome maintenance. Regulation of replication initiation by DDK has long been known to involve phosphorylation of MCM2-7 subunits, but more recent results have indicated that Treslin:MTBP might also be important substrates. Molecular mechanisms by which DDK regulates replisome stability and replicated chromatid cohesion are less well understood, though important new insights have been reported recently. We discuss how the ‘outsourcing’ of activities required for chromosome maintenance to DDK allows CDK to maintain outright control of S phase progression and the cell-cycle phase transitions whilst permitting ongoing chromatin replication and cohesion establishment to be completed and achieved faithfully. Full article
(This article belongs to the Special Issue MTBP-Cellular Roles Underlying Cancer Formation and Disease)
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17 pages, 942 KiB  
Review
The Role of MTBP as a Replication Origin Firing Factor
by Eman Zaffar, Pedro Ferreira, Luis Sanchez-Pulido and Dominik Boos
Biology 2022, 11(6), 827; https://doi.org/10.3390/biology11060827 - 27 May 2022
Cited by 3 | Viewed by 2895
Abstract
The initiation step of replication at replication origins determines when and where in the genome replication machines, replisomes, are generated. Tight control of replication initiation helps facilitate the two main tasks of genome replication, to duplicate the genome accurately and exactly once each [...] Read more.
The initiation step of replication at replication origins determines when and where in the genome replication machines, replisomes, are generated. Tight control of replication initiation helps facilitate the two main tasks of genome replication, to duplicate the genome accurately and exactly once each cell division cycle. The regulation of replication initiation must ensure that initiation occurs during the S phase specifically, that no origin fires more than once per cell cycle, that enough origins fire to avoid non-replicated gaps, and that the right origins fire at the right time but only in favorable circumstances. Despite its importance for genetic homeostasis only the main molecular processes of eukaryotic replication initiation and its cellular regulation are understood. The MTBP protein (Mdm2-binding protein) is so far the last core replication initiation factor identified in metazoan cells. MTBP is the orthologue of yeast Sld7. It is essential for origin firing, the maturation of pre-replicative complexes (pre-RCs) into replisomes, and is emerging as a regulation focus targeted by kinases and by regulated degradation. We present recent insight into the structure and cellular function of the MTBP protein in light of recent structural and biochemical studies revealing critical molecular details of the eukaryotic origin firing reaction. How the roles of MTBP in replication and other cellular processes are mutually connected and are related to MTBP’s contribution to tumorigenesis remains largely unclear. Full article
(This article belongs to the Special Issue MTBP-Cellular Roles Underlying Cancer Formation and Disease)
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