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Genes
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Genome Maintenance and Cancer Predisposition
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Genome Maintenance and Cancer Predisposition

A special issue of Genes (ISSN 2073-4425). This special issue belongs to the section "Molecular Genetics and Genomics".

Deadline for manuscript submissions: closed (15 July 2022) | Viewed by 34426

Special Issue Editor

Dr. Eishi Noguchi

E-Mail Website
Guest Editor
Department of Biochemistry and Molecular Biology, Drexel University College of Medicine, Philadelphia, PA 19102, USA
Interests: DNA replication; DNA repair; genomic instability; cancer; aging
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Eukaryotic organisms have developed a variety of genome maintenance mechanisms to preserve their genetic information. Failure in these mechanisms can results in genomic instability, a hallmark of cancer. Indeed, numerous mutations in genome maintenance genes have been reported to cause cancer predisposition syndromes. Patients with these syndromes display elevated levels of DNA damage and chromosome alterations that lead to genomic instability. At the same time, elevated DNA damage and genomic instability in cancer cells may lead to upregulation of residual DNA repair pathways, which support tumor cell survival. This in turn contributes to therapeutic resistance, particularly for DNA-damaging chemotherapy, leading to the progression of malignancy. Thus, it is of paramount importance to understand cellular programs that preserve genomic integrity and how these programs influence tumor growth.

In this Special Issue, we welcome reviews, new methods, and original articles covering many aspects of genome maintenance and cancer predisposition. These include but are not limited to cell cycle checkpoints, mitosis, DNA damage response, DNA replication, DNA repair, chromatin regulation, and chromosome segregation, many of which are dysregulated during cancer progression. We also encourage you to submit articles regarding genome instability syndromes that are associated with increased cancer incidence.

We look forward to your contributions.

Dr. Eishi Noguchi
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Genes is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2600 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • Genome maintenance
  • Cancer predisposition
  • Genomic instability
  • Genomic integrity
  • Cell cycle
  • Checkpoints
  • DNA replication
  • DNA repair
  • Chromosome organization
  • Chromosome segregation
  • Mitosis

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Published Papers (8 papers)

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Research

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13 pages, 2419 KiB  
Article
GRANT Motif Regulates CENP-A Incorporation and Restricts RNA Polymerase II Accessibility at Centromere
by Hwei Ling Tan and Ee Sin Chen
Genes 2022, 13(10), 1697; https://doi.org/10.3390/genes13101697 - 22 Sep 2022
Cited by 2 | Viewed by 1936
Abstract
Precise chromosome segregation is essential for maintaining genomic stability, and its proper execution centers on the centromere, a chromosomal locus that mounts the kinetochore complex to mediate attachment of chromosomes to the spindle microtubules. The location of the centromere is epigenetically determined by [...] Read more.
Precise chromosome segregation is essential for maintaining genomic stability, and its proper execution centers on the centromere, a chromosomal locus that mounts the kinetochore complex to mediate attachment of chromosomes to the spindle microtubules. The location of the centromere is epigenetically determined by a centromere-specific histone H3 variant, CENP-A. Many human cancers exhibit overexpression of CENP-A, which correlates with occurrence of aneuploidy in these malignancies. Centromeric targeting of CENP-A depends on its histone fold, but recent studies showed that the N-terminal tail domain (NTD) also plays essential roles. Here, we investigated implications of NTD in conferring aneuploidy formation when CENP-A is overexpressed in fission yeast. A series of mutant genes progressively lacking one amino acid of the NTD have been constructed for overexpression in wild-type cells using the intermediate strength nmt41 promoter. Constructs hosting disrupted GRANT (Genomic stability-Regulating site within CENP-A N-Terminus) motif in NTD results in growth retardation, aneuploidy, increased localization to the centromere, upregulated RNA polymerase II accessibility and transcriptional derepression of the repressive centromeric chromatin, suggesting that GRANT residues fine-tune centromeric CENP-A incorporation and restrict RNA polymerase II accessibility. This work highlighted the importance of CENP-A NTD, particularly the GRANT motif, in aneuploidy formation of overexpressed CENP-A in fission yeast. Full article
(This article belongs to the Special Issue Genome Maintenance and Cancer Predisposition)
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16 pages, 4152 KiB  
Article
Identification of Recurrent Chromosome Breaks Underlying Structural Rearrangements in Mammary Cancer Cell Lines
by Natalie C. Senter, Andrew McCulley, Vladimir A. Kuznetsov and Wenyi Feng
Genes 2022, 13(7), 1228; https://doi.org/10.3390/genes13071228 - 11 Jul 2022
Cited by 2 | Viewed by 2330
Abstract
Cancer genomes are characterized by the accumulation of small-scale somatic mutations as well as large-scale chromosomal deletions, amplifications, and complex structural rearrangements. This characteristic is at least partially dependent on the ability of cancer cells to undergo recurrent chromosome breakage. In order to [...] Read more.
Cancer genomes are characterized by the accumulation of small-scale somatic mutations as well as large-scale chromosomal deletions, amplifications, and complex structural rearrangements. This characteristic is at least partially dependent on the ability of cancer cells to undergo recurrent chromosome breakage. In order to address the extent to which chromosomal structural rearrangement breakpoints correlate with recurrent DNA double-strand breaks (DSBs), we simultaneously mapped chromosome structural variation breakpoints (using whole-genome DNA-seq) and spontaneous DSB formation (using Break-seq) in the estrogen receptor (ER)-positive breast cancer cell line MCF-7 and a non-cancer control breast epithelium cell line MCF-10A. We identified concurrent DSBs and structural variation breakpoints almost exclusively in the pericentromeric region of chromosome 16q in MCF-7 cells. We fine-tuned the identification of copy number variation breakpoints on 16q. In addition, we detected recurrent DSBs that occurred in both MCF-7 and MCF-10A. We propose a model for DSB-driven chromosome rearrangements that lead to the translocation of 16q, likely with 10q, and the eventual 16q loss that does not involve the pericentromere of 16q. We present evidence from RNA-seq data that select genes, including SHCBP1, ORC6, and MYLK3, which are immediately downstream from the 16q pericentromere, show heightened expression in MCF-7 cell line compared to the control. Data published by The Cancer Genome Atlas show that all three genes have increased expression in breast tumor samples. We found that SHCBP1 and ORC6 are both strong poor prognosis and treatment outcome markers in the ER-positive breast cancer cohort. We suggest that these genes are potential oncogenes for breast cancer progression. The search for tumor suppressor loss that accompanies the 16q loss ought to be augmented by the identification of potential oncogenes that gained expression during chromosomal rearrangements. Full article
(This article belongs to the Special Issue Genome Maintenance and Cancer Predisposition)
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14 pages, 3308 KiB  
Article
Measuring S-Phase Duration from Asynchronous Cells Using Dual EdU-BrdU Pulse-Chase Labeling Flow Cytometry
by Marta Bialic, Baraah Al Ahmad Nachar, Maria Koźlak, Vincent Coulon and Etienne Schwob
Genes 2022, 13(3), 408; https://doi.org/10.3390/genes13030408 - 24 Feb 2022
Cited by 15 | Viewed by 7099
Abstract
Eukaryotes duplicate their chromosomes during the cell cycle S phase using thousands of initiation sites, tunable fork speed and megabase-long spatio-temporal replication programs. The duration of S phase is fairly constant within a given cell type, but remarkably plastic during development, cell differentiation [...] Read more.
Eukaryotes duplicate their chromosomes during the cell cycle S phase using thousands of initiation sites, tunable fork speed and megabase-long spatio-temporal replication programs. The duration of S phase is fairly constant within a given cell type, but remarkably plastic during development, cell differentiation or various stresses. Characterizing the dynamics of S phase is important as replication defects are associated with genome instability, cancer and ageing. Methods to measure S-phase duration are so far indirect, and rely on mathematical modelling or require cell synchronization. We describe here a simple and robust method to measure S-phase duration in cell cultures using a dual EdU-BrdU pulse-labeling regimen with incremental thymidine chases, and quantification by flow cytometry of cells entering and exiting S phase. Importantly, the method requires neither cell synchronization nor genome engineering, thus avoiding possible artifacts. It measures the duration of unperturbed S phases, but also the effect of drugs or mutations on it. We show that this method can be used for both adherent and suspension cells, cell lines and primary cells of different types from human, mouse and Drosophila. Interestingly, the method revealed that several commonly-used cancer cell lines have a longer S phase compared to untransformed cells. Full article
(This article belongs to the Special Issue Genome Maintenance and Cancer Predisposition)
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Review

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12 pages, 1143 KiB  
Review
Integrating Sister Chromatid Cohesion Establishment to DNA Replication
by Caitlin M. Zuilkoski and Robert V. Skibbens
Genes 2022, 13(4), 625; https://doi.org/10.3390/genes13040625 - 31 Mar 2022
Cited by 4 | Viewed by 3238
Abstract
The intersection through which two fundamental processes meet provides a unique vantage point from which to view cellular regulation. On the one hand, DNA replication is at the heart of cell division, generating duplicate chromosomes that allow each daughter cell to inherit a [...] Read more.
The intersection through which two fundamental processes meet provides a unique vantage point from which to view cellular regulation. On the one hand, DNA replication is at the heart of cell division, generating duplicate chromosomes that allow each daughter cell to inherit a complete copy of the parental genome. Among other factors, the PCNA (proliferating cell nuclear antigen) sliding clamp ensures processive DNA replication during S phase and is essential for cell viability. On the other hand, the process of chromosome segregation during M phase—an act that occurs long after DNA replication—is equally fundamental to a successful cell division. Eco1/Ctf7 ensures that chromosomes faithfully segregate during mitosis, but functions during DNA replication to activate cohesins and thereby establish cohesion between sister chromatids. To achieve this, Eco1 binds PCNA and numerous other DNA replication fork factors that include MCM helicase, Chl1 helicase, and the Rtt101-Mms1-Mms22 E3 ubiquitin ligase. Here, we review the multi-faceted coordination between cohesion establishment and DNA replication. SUMMARY STATEMENT: New findings provide important insights into the mechanisms through which DNA replication and the establishment of sister chromatid cohesion are coupled. Full article
(This article belongs to the Special Issue Genome Maintenance and Cancer Predisposition)
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14 pages, 2276 KiB  
Review
CRL4Cdt2 Ubiquitin Ligase, A Genome Caretaker Controlled by Cdt2 Binding to PCNA and DNA
by Muadz Ahmad Mazian, Kumpei Yamanishi, Mohd Zulhilmi Abdul Rahman, Menega Ganasen and Hideo Nishitani
Genes 2022, 13(2), 266; https://doi.org/10.3390/genes13020266 - 29 Jan 2022
Cited by 3 | Viewed by 4520
Abstract
The ubiquitin ligase CRL4Cdt2 plays a vital role in preserving genomic integrity by regulating essential proteins during S phase and after DNA damage. Deregulation of CRL4Cdt2 during the cell cycle can cause DNA re-replication, which correlates with malignant transformation and tumor [...] Read more.
The ubiquitin ligase CRL4Cdt2 plays a vital role in preserving genomic integrity by regulating essential proteins during S phase and after DNA damage. Deregulation of CRL4Cdt2 during the cell cycle can cause DNA re-replication, which correlates with malignant transformation and tumor growth. CRL4Cdt2 regulates a broad spectrum of cell cycle substrates for ubiquitination and proteolysis, including Cdc10-dependent transcript 1 or Chromatin licensing and DNA replication factor 1 (Cdt1), histone H4K20 mono-methyltransferase (Set8) and cyclin-dependent kinase inhibitor 1 (p21), which regulate DNA replication. However, the mechanism it operates via its substrate receptor, Cdc10-dependent transcript 2 (Cdt2), is not fully understood. This review describes the essential features of the N-terminal and C-terminal parts of Cdt2 that regulate CRL4 ubiquitination activity, including the substrate recognition domain, intrinsically disordered region (IDR), phosphorylation sites, the PCNA-interacting protein-box (PIP) box motif and the DNA binding domain. Drugs targeting these specific domains of Cdt2 could have potential for the treatment of cancer. Full article
(This article belongs to the Special Issue Genome Maintenance and Cancer Predisposition)
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18 pages, 720 KiB  
Review
Impact of G-Quadruplexes and Chronic Inflammation on Genome Instability: Additive Effects during Carcinogenesis
by MaryElizabeth Stein and Kristin A. Eckert
Genes 2021, 12(11), 1779; https://doi.org/10.3390/genes12111779 - 9 Nov 2021
Cited by 10 | Viewed by 3445
Abstract
Genome instability is an enabling characteristic of cancer, essential for cancer cell evolution. Hotspots of genome instability, from small-scale point mutations to large-scale structural variants, are associated with sequences that potentially form non-B DNA structures. G-quadruplex (G4) forming motifs are enriched at structural [...] Read more.
Genome instability is an enabling characteristic of cancer, essential for cancer cell evolution. Hotspots of genome instability, from small-scale point mutations to large-scale structural variants, are associated with sequences that potentially form non-B DNA structures. G-quadruplex (G4) forming motifs are enriched at structural variant endpoints in cancer genomes. Chronic inflammation is a physiological state underlying cancer development, and oxidative DNA damage is commonly invoked to explain how inflammation promotes genome instability. We summarize where G4s and oxidative stress overlap, with a focus on DNA replication. Guanine has low ionization potential, making G4s vulnerable to oxidative damage. Impacts to G4 structure are dependent upon lesion type, location, and G4 conformation. Occasionally, G4s pose a challenge to replicative DNA polymerases, requiring specialized DNA polymerases to maintain genome stability. Therefore, chronic inflammation creates a dual challenge for DNA polymerases to maintain genome stability: faithful G4 synthesis and bypassing unrepaired oxidative lesions. Inflammation is also accompanied by global transcriptome changes that may impact mutagenesis. Several studies suggest a regulatory role for G4s within cancer- and inflammatory-related gene promoters. We discuss the extent to which inflammation could influence gene regulation by G4s, thereby impacting genome instability, and highlight key areas for new investigation. Full article
(This article belongs to the Special Issue Genome Maintenance and Cancer Predisposition)
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24 pages, 2178 KiB  
Review
Developmental Acquisition of p53 Functions
by Sushil K. Jaiswal, Sonam Raj and Melvin L. DePamphilis
Genes 2021, 12(11), 1675; https://doi.org/10.3390/genes12111675 - 23 Oct 2021
Cited by 8 | Viewed by 3895
Abstract
Remarkably, the p53 transcription factor, referred to as “the guardian of the genome”, is not essential for mammalian development. Moreover, efforts to identify p53-dependent developmental events have produced contradictory conclusions. Given the importance of pluripotent stem cells as models of mammalian development, [...] Read more.
Remarkably, the p53 transcription factor, referred to as “the guardian of the genome”, is not essential for mammalian development. Moreover, efforts to identify p53-dependent developmental events have produced contradictory conclusions. Given the importance of pluripotent stem cells as models of mammalian development, and their applications in regenerative medicine and disease, resolving these conflicts is essential. Here we attempt to reconcile disparate data into justifiable conclusions predicated on reports that p53-dependent transcription is first detected in late mouse blastocysts, that p53 activity first becomes potentially lethal during gastrulation, and that apoptosis does not depend on p53. Furthermore, p53 does not regulate expression of genes required for pluripotency in embryonic stem cells (ESCs); it contributes to ESC genomic stability and differentiation. Depending on conditions, p53 accelerates initiation of apoptosis in ESCs in response to DNA damage, but cell cycle arrest as well as the rate and extent of apoptosis in ESCs are p53-independent. In embryonic fibroblasts, p53 induces cell cycle arrest to allow repair of DNA damage, and cell senescence to prevent proliferation of cells with extensive damage. Full article
(This article belongs to the Special Issue Genome Maintenance and Cancer Predisposition)
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9 pages, 1580 KiB  
Review
Gene Amplification and the Extrachromosomal Circular DNA
by Noriaki Shimizu
Genes 2021, 12(10), 1533; https://doi.org/10.3390/genes12101533 - 28 Sep 2021
Cited by 18 | Viewed by 5851
Abstract
Oncogene amplification is closely linked to the pathogenesis of a broad spectrum of human malignant tumors. The amplified genes localize either to the extrachromosomal circular DNA, which has been referred to as cytogenetically visible double minutes (DMs), or submicroscopic episome, or to the [...] Read more.
Oncogene amplification is closely linked to the pathogenesis of a broad spectrum of human malignant tumors. The amplified genes localize either to the extrachromosomal circular DNA, which has been referred to as cytogenetically visible double minutes (DMs), or submicroscopic episome, or to the chromosomal homogeneously staining region (HSR). The extrachromosomal circle from a chromosome arm can initiate gene amplification, resulting in the formation of DMs or HSR, if it had a sequence element required for replication initiation (the replication initiation region/matrix attachment region; the IR/MAR), under a genetic background that permits gene amplification. In this article, the nature, intracellular behavior, generation, and contribution to cancer genome plasticity of such extrachromosomal circles are summarized and discussed by reviewing recent articles on these topics. Such studies are critical in the understanding and treating human cancer, and also for the production of recombinant proteins such as biopharmaceuticals by increasing the recombinant genes in the cells. Full article
(This article belongs to the Special Issue Genome Maintenance and Cancer Predisposition)
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