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 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 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 Multiple roles of DNA2 nuclease/helicase in DNA metabolism, genome stability and human diseases

2019 ◽  
Vol 48 (1) ◽  
pp. 16-35 ◽  
Author(s):  
Li Zheng ◽  
Yuan Meng ◽  
Judith L Campbell ◽  
Binghui Shen
Keyword(s):  
Dna Replication ◽  
Genome Stability ◽  
Multiple Roles ◽  
Tumor Promoter ◽  
Genome Maintenance ◽  
Post Translational Modifications ◽  
Strand Breaks ◽  
Cancer Cell Survival ◽  
Dna Replication And Repair ◽  
End Resection

Abstract DNA2 nuclease/helicase is a structure-specific nuclease, 5′-to-3′ helicase, and DNA-dependent ATPase. It is involved in multiple DNA metabolic pathways, including Okazaki fragment maturation, replication of ‘difficult-to-replicate’ DNA regions, end resection, stalled replication fork processing, and mitochondrial genome maintenance. The participation of DNA2 in these different pathways is regulated by its interactions with distinct groups of DNA replication and repair proteins and by post-translational modifications. These regulatory mechanisms induce its recruitment to specific DNA replication or repair complexes, such as DNA replication and end resection machinery, and stimulate its efficient cleavage of various structures, for example, to remove RNA primers or to produce 3′ overhangs at telomeres or double-strand breaks. Through these versatile activities at replication forks and DNA damage sites, DNA2 functions as both a tumor suppressor and promoter. In normal cells, it suppresses tumorigenesis by maintaining the genomic integrity. Thus, DNA2 mutations or functional deficiency may lead to cancer initiation. However, DNA2 may also function as a tumor promoter, supporting cancer cell survival by counteracting replication stress. Therefore, it may serve as an ideal target to sensitize advanced DNA2-overexpressing cancers to current chemo- and radiotherapy regimens.

scholarly journals CDC45, a novel yeast gene that functions with the origin recognition complex and Mcm proteins in initiation of DNA replication.

1997 ◽  
Vol 17 (2) ◽  
pp. 553-563 ◽  
Author(s):  
L Zou ◽  
J Mitchell ◽  
B Stillman
Keyword(s):  
Dna Replication ◽  
Origin Recognition Complex ◽  
Genetic Interaction ◽  
Sequence Similarity ◽  
Replication Initiation ◽  
Nonpermissive Temperature ◽  
Functional Connection ◽  
Initiation Of Dna Replication ◽  
Mcm Proteins ◽  
Origin Recognition

The CDC45 gene of Saccharomyces cerevisiae was isolated by complementation of the cold-sensitive cdc45-1 mutant and shown to be essential for cell viability. Although CDC45 genetically interacts with a group of MCM genes (CDC46, CDC47, and CDC54), the predicted sequence of its protein product reveals no significant sequence similarity to any known Mcm family member. Further genetic characterization of the cdc45-1 mutant demonstrated that it is synthetically lethal with orc2-1, mcm2-1, and mcm3-1. These results not only reveal a functional connection between the origin recognition complex (ORC) and Cdc45p but also extend the CDC45-MCM genetic interaction to all known MCM family members that were shown to be involved in replication initiation. Initiation of DNA replication in cdc45-1 cells was defective, causing a delayed entry into S phase at the nonpermissive temperature, as well as a high plasmid loss rate which could be suppressed by tandem copies of replication origins. Furthermore, two-dimensional gels directly showed that chromosomal origins fired less frequently in cdc45-1 cells at the nonpermissive temperature. These findings suggest that Cdc45p, ORC, and Mcm proteins act in concert for replication initiation throughout the genome.

scholarly journals Identification of a Preinitiation Step in DNA Replication That Is Independent of Origin Recognition Complex and cdc6, but Dependent on cdk2

1998 ◽  
Vol 140 (2) ◽  
pp. 271-281 ◽  
Author(s):  
Xuequn Helen Hua ◽  
John Newport
Keyword(s):  
Dna Replication ◽  
Origin Recognition Complex ◽  
Minichromosome Maintenance ◽  
Cdk2 Activity ◽  
Proteolytic Pathway ◽  
Egg Extracts ◽  
Dna Replication Origin ◽  
Initiation Of Dna Replication ◽  
Mcm Proteins ◽  
Origin Recognition

Before initiation of DNA replication, origin recognition complex (ORC) proteins, cdc6, and minichromosome maintenance (MCM) proteins bind to chromatin sequentially and form preinitiation complexes. Using Xenopus laevis egg extracts, we find that after the formation of these complexes and before initiation of DNA replication, cdc6 is rapidly removed from chromatin, possibly degraded by a cdk2-activated, ubiquitin-dependent proteolytic pathway. If this displacement is inhibited, DNA replication fails to initiate. We also find that after assembly of MCM proteins into preinitiation complexes, removal of the ORC from DNA does not block the subsequent initiation of replication. Importantly, under conditions in which both ORC and cdc6 protein are absent from preinitiation complexes, DNA replication is still dependent on cdk2 activity. Therefore, the final steps in the process leading to initiation of DNA replication during S phase of the cell cycle are independent of ORC and cdc6 proteins, but dependent on cdk2 activity.

Identification and characterization of the DNA replication origin recognition complex gene family in the silkworm Bombyx mori

2011 ◽  
Vol 31 (5) ◽  
pp. 353-361 ◽  
Author(s):  
Hui-Peng Yang ◽  
Su-Juan Luo ◽  
Yi-Nü Li ◽  
Yao-Zhou Zhang ◽  
Zhi-Fang Zhang
Keyword(s):  
Dna Replication ◽  
Bombyx Mori ◽  
Replication Origin ◽  
Origin Recognition Complex ◽  
Bioinformatic Analysis ◽  
Replication Complex ◽  
Dna Replication Origin ◽  
Rapid Amplification ◽  
Replication Factors ◽  
Origin Recognition

The ORC (origin recognition complex) binds to the DNA replication origin and recruits other replication factors to form the pre-replication complex. The cDNA and genomic sequences of all six subunits of ORC in Bombyx mori (BmORC1–6) were determined by RACE (rapid amplification of cDNA ends) and bioinformatic analysis. The conserved domains were identified in BmOrc1p–6p and the C-terminal of BmOrc6p features a short sequence that may be specific for Lepidoptera. As in other organisms, each of the six BmORC subunits had evolved individually from ancestral genes in early eukaryotes. During embryo development, the six genes were co-regulated, but different ratios of the abundance of mRNAs were observed in 13 tissues of the fifth instar day-6 larvae. Infection by BmNPV (B. mori nucleopolyhedrovirus) initially decreased and then increased the abundance of BmORC. We suggest that some of the BmOrc proteins may have additional functions and that BmOrc proteins participate in the replication of BmNPV.

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.

Methanococcus maripaludis: an archaeon with multiple functional MCM proteins?

2009 ◽  
Vol 37 (1) ◽  
pp. 1-6 ◽  
Author(s):  
Alison D. Walters ◽  
James P.J. Chong
Keyword(s):  
Dna Replication ◽  
Biochemical Characterization ◽  
Model Organisms ◽  
Methanococcus Maripaludis ◽  
Replication Process ◽  
Archaeal Species ◽  
Wide Range ◽  
Eukaryotic Dna ◽  
Good Potential ◽  
Mcm Proteins

There are a large number of proteins involved in the control of eukaryotic DNA replication, which act together to ensure DNA is replicated only once every cell cycle. Key proteins involved in the initiation and elongation phases of DNA replication include the MCM (minchromosome maintenance) proteins, MCM2–MCM7, a family of six related proteins believed to act as the replicative helicase. Genome sequencing has revealed that the archaea possess a simplified set of eukaryotic replication homologues. The complexity of the DNA replication machinery in eukaryotes has led to a number of archaeal species being adapted as model organisms for the study of the DNA replication process. Most archaea sequenced to date possess a single MCM homologue that forms a hexameric complex. Recombinant MCMs from several archaea have been used in the biochemical characterization of the protein, revealing that the MCM complex has ATPase, DNA-binding and -unwinding activities. Unusually, the genome of the methanogenic archaeon Methanococcus maripaludis contains four MCM homologues, all of which contain the conserved motifs required for function. The availability of a wide range of genetic tools for the manipulation of M. maripaludis and the relative ease of growth of this organism in the laboratory makes it a good potential model for studying the role of multiple MCMs in DNA replication.

scholarly journals More than Meets the ISG15: Emerging Roles in the DNA Damage Response and Beyond

Biomolecules ◽  
2020 ◽  
Vol 10 (11) ◽  
pp. 1557
Author(s):  
Zac Sandy ◽  
Isabelle Cristine da Costa ◽  
Christine K. Schmidt
Keyword(s):  
Dna Damage ◽  
Dna Replication ◽  
Dna Damage Response ◽  
Genome Stability ◽  
Post Translational Modifications ◽  
Free Dna ◽  
Damage Response ◽  
Dna Replication And Repair ◽  
Health And Disease ◽  
Interferon Stimulated Gene 15

Maintenance of genome stability is a crucial priority for any organism. To meet this priority, robust signalling networks exist to facilitate error-free DNA replication and repair. These signalling cascades are subject to various regulatory post-translational modifications that range from simple additions of chemical moieties to the conjugation of ubiquitin-like proteins (UBLs). Interferon Stimulated Gene 15 (ISG15) is one such UBL. While classically thought of as a component of antiviral immunity, ISG15 has recently emerged as a regulator of genome stability, with key roles in the DNA damage response (DDR) to modulate p53 signalling and error-free DNA replication. Additional proteomic analyses and cancer-focused studies hint at wider-reaching, uncharacterised functions for ISG15 in genome stability. We review these recent discoveries and highlight future perspectives to increase our understanding of this multifaceted UBL in health and disease.

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