scholarly journals Cyclin E/CDK2: DNA Replication, Replication Stress and Genomic Instability

2021 ◽  
Vol 9 ◽  
Author(s):  
Rafaela Fagundes ◽  
Leonardo K. Teixeira
Keyword(s):  
Cell Cycle ◽  
Dna Replication ◽  
Genomic Instability ◽  
Genome Stability ◽  
Molecular Mechanisms ◽  
Human Cancer ◽  
Cyclin E ◽  
Replication Stress ◽  
Cyclin E1 ◽  
Cdk2 Complex

DNA replication must be precisely controlled in order to maintain genome stability. Transition through cell cycle phases is regulated by a family of Cyclin-Dependent Kinases (CDKs) in association with respective cyclin regulatory subunits. In normal cell cycles, E-type cyclins (Cyclin E1 and Cyclin E2, CCNE1 and CCNE2 genes) associate with CDK2 to promote G1/S transition. Cyclin E/CDK2 complex mostly controls cell cycle progression and DNA replication through phosphorylation of specific substrates. Oncogenic activation of Cyclin E/CDK2 complex impairs normal DNA replication, causing replication stress and DNA damage. As a consequence, Cyclin E/CDK2-induced replication stress leads to genomic instability and contributes to human carcinogenesis. In this review, we focus on the main functions of Cyclin E/CDK2 complex in normal DNA replication and the molecular mechanisms by which oncogenic activation of Cyclin E/CDK2 causes replication stress and genomic instability in human cancer.

scholarly journals Replication Stress, Genomic Instability, and Replication Timing: A Complex Relationship

2021 ◽  
Vol 22 (9) ◽  
pp. 4764
Author(s):  
Lina-Marie Briu ◽  
Chrystelle Maric ◽  
Jean-Charles Cadoret
Keyword(s):  
Cell Cycle ◽  
Genomic Instability ◽  
Transcriptional Activity ◽  
Molecular Mechanisms ◽  
Replication Timing ◽  
Replication Stress ◽  
Complex Relationship ◽  
New Biomarkers ◽  
Cis And Trans ◽  
Nuclear Processes

The replication-timing program constitutes a key element of the organization and coordination of numerous nuclear processes in eukaryotes. This program is established at a crucial moment in the cell cycle and occurs simultaneously with the organization of the genome, thus indicating the vital significance of this process. With recent technological achievements of high-throughput approaches, a very strong link has been confirmed between replication timing, transcriptional activity, the epigenetic and mutational landscape, and the 3D organization of the genome. There is also a clear relationship between replication stress, replication timing, and genomic instability, but the extent to which they are mutually linked to each other is unclear. Recent evidence has shown that replication timing is affected in cancer cells, although the cause and consequence of this effect remain unknown. However, in-depth studies remain to be performed to characterize the molecular mechanisms of replication-timing regulation and clearly identify different cis- and trans-acting factors. The results of these studies will potentially facilitate the discovery of new therapeutic pathways, particularly for personalized medicine, or new biomarkers. This review focuses on the complex relationship between replication timing, replication stress, and genomic instability.

scholarly journals LIM Protein Ajuba associates with the RPA complex through direct and cell cycle-dependent interaction with the RPA70 subunit

2017 ◽  
Author(s):  
Sandy Fowler ◽  
Pascal Maguin ◽  
Sampada Kalan ◽  
Diego Loayza
Keyword(s):  
Cell Cycle ◽  
Dna Replication ◽  
Genome Stability ◽  
Replication Stress ◽  
Cellular Transformation ◽  
Early Event ◽  
Lim Protein ◽  
Show Evidence ◽  
Dna Replication Stress ◽  
Cycle Dependent

AbstractDNA damage response pathways are essential for genome stability and cell survival. Specifically, the ATR kinase is activated by DNA replication stress. An early event in this activation is the recruitment and phosphorylation of RPA, a single stranded DNA binding complex composed of three subunits, RPA70,RPA32 and RPA14. We have previously shown that the LIM protein Ajuba associates with RPA, and that depletion of Ajuba leads to potent activation of ATR. In this study, we show evidence that the Ajuba-RPA interaction occurs through direct protein contact with RPA70, and that their association is cell cycle-regulated and is reduced upon DNA replication stress. We propose a model in which Ajuba negatively regulates the ATR pathway by directly interacting with RPA70, thereby preventing an inappropriate ATR activation. Our results provide a framework to understand the mechanism of regulation of ATR in human cells, which is important to prevent cellular transformation and tumorigenesis.

scholarly journals H3.1K27me1 maintains transcriptional silencing and genome stability by preventing GCN5-mediated histone acetylation

2020 ◽  
Author(s):  
Jie Dong ◽  
Chantal LeBlanc ◽  
Axel Poulet ◽  
Benoit Mermaz ◽  
Gonzalo Villarino ◽  
...  
Keyword(s):  
Dna Replication ◽  
Histone Acetylation ◽  
Genomic Instability ◽  
Genome Stability ◽  
Molecular Mechanisms ◽  
Histone Acetyltransferase ◽  
Transcriptional Silencing ◽  
Histone Acetyltransferase Gcn5 ◽  
Lysine Residues

AbstractIn plants, genome stability is maintained during DNA replication by the H3.1K27 methyltransferases ATXR5 and ATXR6, which catalyze the deposition of K27me1 on replicationdependent H3.1 variants. Loss of H3.1K27me1 in atxr5 atxr6 double mutants leads to heterochromatin defects, including transcriptional de-repression and genomic instability, but the molecular mechanisms involved remain largely unknown. In this study, we identified the conserved histone acetyltransferase GCN5 as a mediator of transcriptional de-repression and genomic instability in the absence of H3.1K27me1. GCN5 is part of a SAGA-like complex in plants that requires ADA2b and CHR6 to mediate the heterochromatic defects of atxr5 atxr6 mutants. Our results show that Arabidopsis GCN5 acetylates multiple lysine residues on H3.1 variants in vitro, but that H3.1K27 and H3.1K36 play key roles in inducing genomic instability in the absence of H3.1K27me1. Overall, this work reveals a key molecular role for H3.1K27me1 in maintaining genome stability by restricting histone acetylation in plants.

Multiple mechanisms account for genomic instability and molecular mutation in neoplastic transformation

1995 ◽  
Vol 41 (5) ◽  
pp. 644-657 ◽  
Author(s):  
W B Coleman ◽  
G J Tsongalis
Keyword(s):  
Cell Cycle ◽  
Dna Repair ◽  
Dna Replication ◽  
Genomic Instability ◽  
Molecular Mechanisms ◽  
Target Genes ◽  
Neoplastic Transformation ◽  
Molecular Alteration ◽  
Cellular Processes ◽  
Genes Encoding

Abstract Neoplastic cells typically possess numerous genomic mutations and chromosomal aberrations, including point mutations, gene amplifications and deletions, and replication errors. Acquisition of such genomic instability may represent an early step in the process of carcinogenesis. Proteins involved in DNA replication, DNA repair, cell cycle progression, and others are all components of complex overlapping biochemical pathways that function to maintain cellular homeostasis. Therefore, mutational alteration of genes encoding proteins involved in these cellular processes could contribute to genomic instability. Loss of normal cellular mechanisms that guard against genomic mutation and the ensuing genomic instability might lead to accumulation of multiple stable mutations in the genome of affected cells, perhaps resulting in neoplastic transformation when some critical number of transformation-related target genes become damaged. Thus, interactions of fundamental cellular processes play significant roles in sustaining cellular normality, and alteration of any of these homeostatic processes could entrain cells to the progressive genomic instability and phenotypic evolution characteristic of carcinogenesis. Here, we discuss possible molecular mechanisms governing DNA mutation and genomic instability in genetically normal cells that might account for the acquisition of genomic instability in somatic cells, leading to the development of neoplasia. These include (a) molecular alteration of genes encoding DNA repair enzymes, (b) molecular alteration of genes responsible for cell-cycle control mechanisms, and (c) direct molecular alteration of dominantly transforming cellular protooncogenes. We also discuss normal cellular processes involved with DNA replication and repair that can contribute to the mutational alteration of critical genes: e.g., slow repair of damaged DNA in specific genes, and the timing of normal gene-specific replication.

scholarly journals Regulation of DNA Replication Licensing and Re-Replication by Cdt1

2021 ◽  
Vol 22 (10) ◽  
pp. 5195
Author(s):  
Hui Zhang
Keyword(s):  
Cell Cycle ◽  
Dna Damage ◽  
Dna Replication ◽  
Genome Stability ◽  
E3 Ligase ◽  
S Phase ◽  
Replication Initiation ◽  
Nuclear Antigen ◽  
Repair Synthesis ◽  
Ubiquitin E3 Ligase

In eukaryotic cells, DNA replication licensing is precisely regulated to ensure that the initiation of genomic DNA replication in S phase occurs once and only once for each mitotic cell division. A key regulatory mechanism by which DNA re-replication is suppressed is the S phase-dependent proteolysis of Cdt1, an essential replication protein for licensing DNA replication origins by loading the Mcm2-7 replication helicase for DNA duplication in S phase. Cdt1 degradation is mediated by CRL4Cdt2 ubiquitin E3 ligase, which further requires Cdt1 binding to proliferating cell nuclear antigen (PCNA) through a PIP box domain in Cdt1 during DNA synthesis. Recent studies found that Cdt2, the specific subunit of CRL4Cdt2 ubiquitin E3 ligase that targets Cdt1 for degradation, also contains an evolutionarily conserved PIP box-like domain that mediates the interaction with PCNA. These findings suggest that the initiation and elongation of DNA replication or DNA damage-induced repair synthesis provide a novel mechanism by which Cdt1 and CRL4Cdt2 are both recruited onto the trimeric PCNA clamp encircling the replicating DNA strands to promote the interaction between Cdt1 and CRL4Cdt2. The proximity of PCNA-bound Cdt1 to CRL4Cdt2 facilitates the destruction of Cdt1 in response to DNA damage or after DNA replication initiation to prevent DNA re-replication in the cell cycle. CRL4Cdt2 ubiquitin E3 ligase may also regulate the degradation of other PIP box-containing proteins, such as CDK inhibitor p21 and histone methylase Set8, to regulate DNA replication licensing, cell cycle progression, DNA repair, and genome stability by directly interacting with PCNA during DNA replication and repair synthesis.

scholarly journals Novel localization and possible functions of cyclin E in early sea urchin development

2002 ◽  
Vol 115 (1) ◽  
pp. 113-121 ◽  
Author(s):  
Bradley J. Schnackenberg ◽  
William F. Marzluff
Keyword(s):  
Cell Cycle ◽  
Dna Replication ◽  
Sea Urchin ◽  
Kinase Activity ◽  
Cyclin E ◽  
Sperm Head ◽  
Mitotic Spindles ◽  
Paternal Genome ◽  
Cell Cycles ◽  
Cdk2 Activity

In somatic cells, cyclin E-cdk2 activity oscillates during the cell cycle and is required for the regulation of the G1/S transition. Cyclin E and its associated kinase activity remain constant throughout early sea urchin embryogenesis, consistent with reports from studies using several other embryonic systems. Here we have expanded these studies and show that cyclin E rapidly and selectively enters the sperm head after fertilization and remains concentrated in the male pronucleus until pronuclear fusion, at which time it disperses throughout the zygotic nucleus. We also show that cyclin E is not concentrated at the centrosomes but is associated with condensed chromosomes throughout mitosis for at least the first four cell cycles. Isolated mitotic spindles are enriched for cyclin E and cdk2, which are localized to the chromosomes. The chromosomal cyclin E is associated with active kinase during mitosis. We propose that cyclin E may play a role in the remodeling of the sperm head and re-licensing of the paternal genome after fertilization. Furthermore, cyclin E does not need to be degraded or dissociated from the chromosomes during mitosis; instead, it may be required on chromosomes during mitosis to immediately initiate the next round of DNA replication.

Sign in / Sign up

Export Citation Format

Share Document