scholarly journals Opposing roles for DNA replication initiator proteins ORC1 and CDC6 in control of Cyclin E gene transcription

eLife ◽  
2016 ◽  
Vol 5 ◽  
Author(s):  
Manzar Hossain ◽  
Bruce Stillman
Keyword(s):  
Cell Division ◽  
Dna Replication ◽  
Genome Stability ◽  
Origin Recognition Complex ◽  
Cyclin E ◽  
Large Subunit ◽  
Rb Protein ◽  
E Gene ◽  
Opposing Effects ◽  
Replication Initiator

Newly born cells either continue to proliferate or exit the cell division cycle. This decision involves delaying expression of Cyclin E that promotes DNA replication. ORC1, the Origin Recognition Complex (ORC) large subunit, is inherited into newly born cells after it binds to condensing chromosomes during the preceding mitosis. We demonstrate that ORC1 represses Cyclin E gene (CCNE1) transcription, an E2F1 activated gene that is also repressed by the Retinoblastoma (RB) protein. ORC1 binds to RB, the histone methyltransferase SUV39H1 and to its repressive histone H3K9me3 mark. ORC1 cooperates with SUV39H1 and RB protein to repress E2F1-dependent CCNE1 transcription. In contrast, the ORC1-related replication protein CDC6 binds Cyclin E-CDK2 kinase and in a feedback loop removes RB from ORC1, thereby hyper-activating CCNE1 transcription. The opposing effects of ORC1 and CDC6 in controlling the level of Cyclin E ensures genome stability and a mechanism for linking directly DNA replication and cell division commitment.

scholarly journals Post-Translational Modifications of the Mini-Chromosome Maintenance Proteins in DNA Replication

Genes ◽  
2019 ◽  
Vol 10 (5) ◽  
pp. 331 ◽  
Author(s):  
Li ◽  
Xu
Keyword(s):  
Cell Division ◽  
Dna Replication ◽  
Genome Stability ◽  
Origin Recognition Complex ◽  
Replication Process ◽  
Post Translational Modifications ◽  
Replication Complex ◽  
Therapeutic Implications ◽  
Therapeutic Development ◽  
Mcm Proteins

The eukaryotic mini-chromosome maintenance (MCM) complex, composed of MCM proteins 2–7, is the core component of the replisome that acts as the DNA replicative helicase to unwind duplex DNA and initiate DNA replication. MCM10 tightly binds the cell division control protein 45 homolog (CDC45)/MCM2–7/ DNA replication complex Go-Ichi-Ni-San (GINS) (CMG) complex that stimulates CMG helicase activity. The MCM8–MCM9 complex may have a non-essential role in activating the pre-replicative complex in the gap 1 (G1) phase by recruiting cell division cycle 6 (CDC6) to the origin recognition complex (ORC). Each MCM subunit has a distinct function achieved by differential post-translational modifications (PTMs) in both DNA replication process and response to replication stress. Such PTMs include phosphorylation, ubiquitination, small ubiquitin-like modifier (SUMO)ylation, O-N-acetyl-D-glucosamine (GlcNAc)ylation, and acetylation. These PTMs have an important role in controlling replication progress and genome stability. Because MCM proteins are associated with various human diseases, they are regarded as potential targets for therapeutic development. In this review, we summarize the different PTMs of the MCM proteins, their involvement in DNA replication and disease development, and the potential therapeutic implications.

scholarly journals Structural basis of DNA replication origin recognition by human Orc6 protein binding with DNA

2020 ◽  
Vol 48 (19) ◽  
pp. 11146-11161
Author(s):  
Naining Xu ◽  
Yingying You ◽  
Changdong Liu ◽  
Maxim Balasov ◽  
Lee Tung Lun ◽  
...  
Keyword(s):  
Dna Replication ◽  
Dna Binding ◽  
Solution Structure ◽  
Origin Recognition Complex ◽  
Structural Basis ◽  
Dna Replication Origin ◽  
Dna Alterations ◽  
Replication Initiator ◽  
Binding Subunit ◽  
Origin Recognition

Abstract The six-subunit origin recognition complex (ORC), a DNA replication initiator, defines the localization of the origins of replication in eukaryotes. The Orc6 subunit is the smallest and the least conserved among ORC subunits. It is required for DNA replication and essential for viability in all species. Orc6 in metazoans carries a structural homology with transcription factor TFIIB and can bind DNA on its own. Here, we report a solution structure of the full-length human Orc6 (HsOrc6) alone and in a complex with DNA. We further showed that human Orc6 is composed of three independent domains: N-terminal, middle and C-terminal (HsOrc6-N, HsOrc6-M and HsOrc6-C). We also identified a distinct DNA-binding domain of human Orc6, named as HsOrc6-DBD. The detailed analysis of the structure revealed novel amino acid clusters important for the interaction with DNA. Alterations of these amino acids abolish DNA-binding ability of Orc6 and result in reduced levels of DNA replication. We propose that Orc6 is a DNA-binding subunit of human/metazoan ORC and may play roles in targeting, positioning and assembling the functional ORC at the origins.

scholarly journals Dynamics of pre-replication complex proteins during the cell division cycle

2004 ◽  
Vol 359 (1441) ◽  
pp. 7-16 ◽  
Author(s):  
Supriya G. Prasanth ◽  
Juan Méndez ◽  
Kannanganattu V. Prasanth ◽  
Bruce Stillman
Keyword(s):  
Cell Cycle ◽  
Cell Division ◽  
Dna Replication ◽  
Origin Recognition Complex ◽  
Cell Division Cycle ◽  
Vital Functions ◽  
A Cell ◽  
Bona Fide ◽  
Mcm Proteins ◽  
Key Participants

Replication of the human genome every time a cell divides is a highly coordinated process that ensures accurate and efficient inheritance of the genetic information. The molecular mechanism that guarantees that many origins of replication fire only once per cell–cycle has been the area of intense research. The origin recognition complex (ORC) marks the position of replication origins in the genome and serves as the landing pad for the assembly of a multiprotein, pre–replicative complex (pre–RC) at the origins, consisting of ORC, cell division cycle 6 (Cdc6), Cdc10–dependent transcript (Cdt1) and mini–chromosome maintenance (MCM) proteins. The MCM proteins serve as key participants in the mechanism that limits eukaryotic DNA replication to once–per–cell–cycle and its binding to the chromatin marks the final step of pre–RC formation, a process referred to as ‘replication licensing’. We present data demonstrating how the MCM proteins associate with the chromatin during the G1 phase, probably defining pre–RCs and then anticipate replication fork movement in a precisely coordinated manner during the S phase of the cell cycle. The process of DNA replication must also be carefully coordinated with other cell–cycle processes including mitosis and cytokinesis. Some of the proteins that control initiation of DNA replication are likely to interact with the pathways that control these important cell–cycle transitions. Herein, we discuss the participation of human ORC proteins in other vital functions, in addition to their bona fide roles in replication.

scholarly journals The human origin recognition complex is essential for pre-RC assembly, mitosis, and maintenance of nuclear structure

eLife ◽  
2021 ◽  
Vol 10 ◽  
Author(s):  
Hsiang-Chen Chou ◽  
Kuhulika Bhalla ◽  
Osama EL Demerdesh ◽  
Olaf Klingbeil ◽  
Kaarina Hanington ◽  
...  
Keyword(s):  
Cell Division ◽  
Dna Replication ◽  
Origin Recognition Complex ◽  
Cellular Proliferation ◽  
Nuclear Organization ◽  
Cell Division Cycle ◽  
G1 Phase ◽  
Human Origin ◽  
Multiple Cell ◽  
Origin Recognition

The origin recognition complex (ORC) cooperates with CDC6, MCM2-7, and CDT1 to form pre-RC complexes at origins of DNA replication. Here, using tiling-sgRNA CRISPR screens, we report that each subunit of ORC and CDC6 is essential in human cells. Using an auxin-inducible degradation system, we created stable cell lines capable of ablating ORC2 rapidly, revealing multiple cell division cycle phenotypes. The primary defects in the absence of ORC2 were cells encountering difficulty in initiating DNA replication or progressing through the cell division cycle due to reduced MCM2-7 loading onto chromatin in G1 phase. The nuclei of ORC2-deficient cells were also large, with decompacted heterochromatin. Some ORC2-deficient cells that completed DNA replication entered into, but never exited mitosis. ORC1 knockout cells also demonstrated extremely slow cell proliferation and abnormal cell and nuclear morphology. Thus, ORC proteins and CDC6 are indispensable for normal cellular proliferation and contribute to nuclear organization.

Efficiency and equity in origin licensing to ensure complete DNA replication

2021 ◽  
Author(s):  
Liu Mei ◽  
Jeanette Gowen Cook
Keyword(s):  
Cell Cycle ◽  
Cell Division ◽  
Dna Replication ◽  
Genome Stability ◽  
S Phase ◽  
Replication Initiation ◽  
G1 Phase ◽  
Dna Replication Initiation ◽  
Origin Licensing ◽  
Dna Replication Origins

The cell division cycle must be strictly regulated during both development and adult maintenance, and efficient and well-controlled DNA replication is a key event in the cell cycle. DNA replication origins are prepared in G1 phase of the cell cycle in a process known as origin licensing which is essential for DNA replication initiation in the subsequent S phase. Appropriate origin licensing includes: (1) Licensing enough origins at adequate origin licensing speed to complete licensing before G1 phase ends; (2) Licensing origins such that they are well-distributed on all chromosomes. Both aspects of licensing are critical for replication efficiency and accuracy. In this minireview, we will discuss recent advances in defining how origin licensing speed and distribution are critical to ensure DNA replication completion and genome stability.

scholarly journals Systemic Analysis of the Dna Replication Regulators Origin Recognition Complex in Lung Adenocarcinomas Identifies Prognostic and Expression Significance

2021 ◽  
Author(s):  
Yun-bo Deng ◽  
Juan Chen ◽  
Xian-yu Luo ◽  
Tian Zeng ◽  
Dong-mei Ye ◽  
...  
Keyword(s):  
Protein Structure ◽  
Dna Replication ◽  
Origin Recognition Complex ◽  
Functional Enrichment ◽  
Ppi Network ◽  
Immune Infiltration ◽  
Systemic Analysis ◽  
Lung Adenocarcinomas ◽  
Replication Initiator ◽  
Origin Recognition

Abstract Background: Origin recognition complex (ORC) 1, ORC2, ORC3, ORC4, ORC5 and ORC6, form a replication-initiator complex to mediate DNA replication, which play a key role in carcinogenesis, while their role in lung adenocarcinomas (LUAD) remains poorly understood.Methods: We confirmed the transcriptional and post-transcriptional levels, DNA alteration, DNA methylation, miRNA network, protein structure, PPI network, functional enrichment, immune infiltration and prognostic value of ORCs in LUAD based on Oncomine, GEPIA, HPA, cBioportal, TCGA, GeneMANIA, Metascape, KM-plot, GENT2, and TIMER database. Results: ORC mRNA and protein were both enhanced obviously based on Oncomine, Ualcan, GEPIA, TCGA and HPA database. Furthermore, ORC1 and ORC6 have significant prognostic values for LUAD patients based on GEPIA database. Protein structure, PPI network, functional enrichment and immune infiltration analysis indicated that ORC complex cooperatively accelerate the LUAD development by promoting DNA replication, cellular senescence and metabolic process. Conclusion: the ORC complex has an important prognostic and expression significance for LUAD patients.

scholarly journals Systemic Analysis of the DNA Replication Regulators Origin Recognition Complex in Lung Adenocarcinomas Identifies Prognostic and Expression Significance

2021 ◽  
Author(s):  
Juan Chen ◽  
Juan Zou ◽  
Juan Zeng ◽  
Tian Zeng ◽  
Qi-hao Hu ◽  
...  
Keyword(s):  
Protein Structure ◽  
Dna Replication ◽  
Origin Recognition Complex ◽  
Functional Enrichment ◽  
Ppi Network ◽  
Immune Infiltration ◽  
Systemic Analysis ◽  
Lung Adenocarcinomas ◽  
Replication Initiator ◽  
Origin Recognition

Abstract Background: Origin recognition complex (ORC) 1, ORC2, ORC3, ORC4, ORC5 and ORC6, form a replication-initiator complex to mediate DNA replication, which play a key role in carcinogenesis, while their role in lung adenocarcinomas (LUAD) remains poorly understood.Methods: We confirmed the transcriptional and post-transcriptional levels, DNA alteration, DNA methylation, miRNA network, protein structure, PPI network, functional enrichment, immune infiltration and prognostic value of ORCs in LUAD based on Oncomine, GEPIA, HPA, cBioportal, TCGA, GeneMANIA, Metascape, KM-plot, GENT2, and TIMER database. Results: ORC mRNA and protein were both enhanced obviously based on Oncomine, Ualcan, GEPIA, TCGA and HPA database. Furthermore, ORC1 and ORC6 have significant prognostic values for LUAD patients based on GEPIA database. Protein structure, PPI network, functional enrichment and immune infiltration analysis indicated that ORC complex cooperatively accelerate the LUAD development by promoting DNA replication, cellular senescence and metabolic process. Conclusion: the ORC complex has an important prognostic and expression significance for LUAD patients.

scholarly journals Human Origin Recognition Complex Large Subunit Is Degraded by Ubiquitin-Mediated Proteolysis after Initiation of DNA Replication

2002 ◽  
Vol 9 (3) ◽  
pp. 481-491 ◽  
Author(s):  
Juan Méndez ◽  
X.Helena Zou-Yang ◽  
So-Young Kim ◽  
Masumi Hidaka ◽  
William P. Tansey ◽  
...  
Keyword(s):  
Dna Replication ◽  
Origin Recognition Complex ◽  
Large Subunit ◽  
Human Origin ◽  
Initiation Of Dna Replication ◽  
Origin Recognition
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