DNA re-replication

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Overview of normal chromosome duplication in the cell cycle Overview of chromosome duplication in the cell cycle.svg
Overview of normal chromosome duplication in the cell cycle

DNA re-replication (or simply rereplication) is an undesirable and possibly fatal occurrence in eukaryotic cells in which the genome is replicated more than once per cell cycle. [1] Rereplication is believed to lead to genomic instability and has been implicated in the pathologies of a variety of human cancers. [2] To prevent rereplication, eukaryotic cells have evolved multiple, overlapping mechanisms to inhibit chromosomal DNA from being partially or fully rereplicated in a given cell cycle. These control mechanisms rely on cyclin-dependent kinase (CDK) activity. [1] DNA replication control mechanisms cooperate to prevent the relicensing of replication origins and to activate cell cycle and DNA damage checkpoints. [2] DNA rereplication must be strictly regulated to ensure that genomic information is faithfully transmitted through successive generations.

Contents

Initiating replication at origins

Replication of DNA always begins at an origin of replication. In yeast, the origins contain autonomously replicating sequences (ARS), distributed throughout the chromosome about 30 kb from each other. They allow replication of DNA wherever they are placed. Each one is 100-200 bp long, and the A element is one of the most conserved stretches. Along with other conserved B elements, they form the section where the origin recognition complexes (ORCs) assemble to begin replication. The repetition of these sequences may be the most important to origin recognition.

In animal cells, replication origins may seem to be randomly placed throughout the chromosome, sometimes even acting as ARSs, but local chromatin structure plays a large role in determining where replication will occur. The replication origins are not distributed evenly throughout the chromosome. Replicon clusters, containing 20-80 origins per cluster, are activated at the same time during S phase. Although they are all activated during S phase, heterochromatin tends to be replicated in late S phase, as they are more difficult to access than euchromatin. Epigenetic factors also have a large influence on what gets replicated and when it gets replicated. [3]

Origin licensing

All known mechanisms that prevent DNA rereplication in eukaryotic organisms inhibit origin licensing. [1] Origin licensing is the preliminary step for normal replication initiation during late G1 and early S phase and involves the recruitment of the pre-replicative complex (pre-RC) to the replication origins. Licensing begins with the binding of the multi-subunit ATPase, the origin recognition complex (ORC), to the DNA at the replication origins. [4] Once bound to chromatin the ORC recruits the AAA+ ATPase Cdc6 and the coiled-coil domain protein Cdt1. Cdt1 binding and the ATPase activity of ORC and Cdc6 facilitate the loading of the minichromosome maintenance (MCM) proteins 2-7 onto the chromatin. [1] The MCM complex is the DNA helicase that opens the helix at the replication origin and unwinds the two strands as the replication forks travel along the DNA. [5] Elevated CDK activity at the end of G1 triggers the firing of the origins and the dismantling of the pre-RCs. High CDK levels, which are maintained until the end of mitosis, inhibit or destroy pre-RC components and prevent the origin from relicensing. A new MCM complex cannot be loaded onto the origin until the pre-RC subunits are reactivated with the decline of CDK activity at the end of mitosis. Thus, CDKs serve a dual role in the regulation of eukaryotic DNA replication: elevated CDK activity initiates replication at the origins and prevents rereplication by inhibiting origin re-licensing. [6] [7] [8] This ensures that no replication origin fires twice in the same cell cycle. [5]

Two-state model for DNA replication regulation

S. cerevisiae origin in the prereplicative state. Assembly of the pre-replicative complex (pre-RC) readies the origin for firing. Origin Licensing.png
S. cerevisiae origin in the prereplicative state. Assembly of the pre-replicative complex (pre-RC) readies the origin for firing.
S. cerevisiae origin in the postreplicative state. CDK-mediated phosphorylation of the pre-RC components prevents origins from re-licensing. Inhibition of pre-RC assembly.png
S. cerevisiae origin in the postreplicative state. CDK-mediated phosphorylation of the pre-RC components prevents origins from re-licensing.

Early experimental evidence on the regulation of DNA replication suggests that replication origins exist in one of two states during the cell cycle: a prereplicative state in G1 and a postreplicative state from the moment of initiation until passage through mitosis. [1] Origins of replication alternate between these two distinct states during the cell cycle. [9] A licensing factor which is required for replication initiation binds to origins in the prereplicative state. At the G1/S transition, the factor is inactivated and cannot be restored until the cell cycle has concluded. [10] The identification and characterization of the ORC, Cdc6, Cdt1, and the MCM complex proteins as the licensing factor gives credence to this model and suggests a means by which the oscillatory nature of CDKs in the cell cycle can regulate rereplication. [1]

Replication regulation

Budding yeast

Rereplication regulation is best understood in budding yeast. Saccharomyces cerevisiae cells prevent rereplication by directly regulating pre-RC assembly through the CDK-mediated phosphorylation of the pre-RC components Cdc6, MCM2-7, and the ORC subunits. [5] The phosphorylation of these components is initiated at the onset of S phase and is maintained throughout the rest of the cell cycle as CDK activity remains high. Phosphorylated Cdc6 is bound by the ubiquitin-protein ligase SCF which leads to its proteolytic degradation. CDK-dependent phosphorylation of the MCM2-7 proteins results in the complex's export from the nucleus. (Cdt1 which associates with the MCM complex is similarly exported from the nucleus). Phosphorylation of the ORC subunits presumably disrupts the ORC's ability to bind other pre-RC components. [5] Thus, multiple mechanisms ensure that the pre-RC cannot be reassembled on postreplicative origins.

Note: Since origins fire at different times throughout S phase, it is crucial that the inhibitory mechanisms that prevent new MCM2-7 recruitment do not destabilize existing pre-RCs. Pre-RCs can remain assembled on origins that haven't fired even though rereplication inhibitory mechanisms are inhibiting or destroying pre-RC components.

Other organisms

Although CDK regulation of pre-RC assembly appears to be highly evolutionarily conserved, some differences across organisms are noted. In multicellular eukaryotes pre-RC assembly is regulated by the anaphase-promoting complex (APC) in addition to CDKs. APC, an E3 enzyme, ubiquitinates the protein geminin and targets it for degradation. [5] Geminin normally prevents origin licensing by binding to and inhibiting Cdt1. In G1, APC activity is adequate to suppress the accumulation of geminin, thereby indirectly promoting pre-RC assembly. At the end of G1, APC is inactivated and geminin can accumulate and prevent origin re-licensing.

Cdt1 is usually upregulated by E2F-mediated transcriptional activation and by binding of human acetylase to Orc1. Proteolytic degradation of Cdt1 is a conserved mechanism in various higher order eukaryotes as well. Cdt1 is degraded through the Cul4–Ddb1–Cdt2 E3 ubiquitin ligase complex so that DNA licensing control is maintained in S and G2. Cdt1 is an important regulatory protein, and evolution has led to different pathways of regulation in different organisms. Overexpression of Cdt1 or incactivation of Geminin can lead to re-replication, as undegraded Cdt1 will induce pre-RC assembly. [11]

Pre-RC regulation in most animals is still not well understood. [5]

Consequences of rereplication in eukaryotic cells

Rereplication and mitotic failure are generally not programmed events, but rather result spontaneously from defects in the cell cycle machinery. [1] Rereplication appears to give rise to dsDNA breaks which triggers a DNA damage response and arrests cells in G2. [12] The checkpoint effectively causes a permanent cell cycle arrest and eventual apoptosis. [13]

Rereplication can be experimentally induced by simultaneously disrupting several of the mechanisms that prevent origin re-licensing. For example, deregulation of the ORC, MCM2-7 and Cdc6 mechanisms can induce rereplication in budding yeast cells. [14]

Note: Recent evidence suggests that although overlapping, the multiple replication regulation mechanisms should not be considered as functionally redundant; although a single mechanism may repress rereplication at greater than 99% efficiency, it may not be sufficient to maintain genome stability over many generations. [15] Instead, it is believed[ by whom? ] that the multiplicative effect of many overlapping mechanisms is what sufficiently prevents rereplication and ensures the faithful transmission of a cell's genome.

Preventing rereplication

Cells with replication stress activate replication checkpoints so that S phase is delayed and slows down the transition to G2/M phase. When replicative stress is recognized by U-2-OS cells, human osteosarcoma cell lines with wild-type retinoblastoma (RB) and p53, the ATM/ATR-regulated DNA damage network is activated. [16] This checkpoint response activates due to overexpression of cyclin E, which has been shown to be important in regulating the licensing system. [17] When cyclin E is overexpressed in U-2-OS cell lines, the ATM/ATR-regulated DNA damage network results in increases in Ser 15-phosphorylated p53, γ-H2AX, and Ser 966-phosphorylated cohesin SMC1. [16] The DNA re-replication response is different from the response taken when damage is due to oxygen radical generation. Damage from oxygen radical generations leads to a response from the Myc oncogene, which phosphorylates p53 and H2AX. [16]

The ATM/ATR DNA damage network will also respond to cases where there is an overexpression of Cdt1. Overexpression of Cdt1 leads to accumulation of ssDNA and DSBs. Ataxia telangiectasia and Rad3 related (ATR) is activated earlier when it detects ssDNA in the earlier phases of DNA re-replication. ATR phosphorylates downstream replication factors, such as RPA2 and MCM2 or through modulation of Rb or p53. Ataxia telangiectasia mutated (ATM) activates after a larger amount of DSBs is detected at later stages of DNA re-replication. While ATM plays a role in cell cycle arrest, apoptosis, and senescence, it is also suspected to play a role in mediating DSB repair, but the exact mechanisms are not understood yet. [11]

Rereplication in cancer

Rereplication has been implicated in tumorigenesis in model organisms and humans. Replication initiation proteins are overexpressed in tissue samples from several types of human cancers [1] [18] [19] and experimental overexpression of Cdt1 and Cdc6 can cause tumor development in mouse cells. [20] [21] [22] Similarly, Geminin ablation in knockout mice has been reported to enhance tumor formation. [23] Further, these studies indicate that rereplication can result in an increase in aneuploidy, chromosomal fusions, and DNA breaks. [24] A thorough understanding of the regulatory replication mechanisms is important for the development of novel cancer treatments.

In yeast, increased activity of G1 CDK activity usually inhibits the assembly of pre-RCs and entry into S phase with less active origins, but in cancer cells, p53 and Rb/E2F pathways are deregulated and allow entry into S phase with a reduced amount of active origins. This leads to double-strand breaks in the DNA, increased recombination, and incorrect chromosomal arrangements. The mechanism by which this damage occurs is still not known. One possibility is that reduced origin activation leads to incomplete DNA replication. Significant re-replication is only observed when all CDK regulatory pathways are inhibited. [25]

In mammalian cells, Cdt1 and Cdc6 are much more important to re-replication regulation. [25] Overexpression of Cdt1 and Cdc6 were found in 43/75 cases of non-small cell lung carcinomas. [11] Targeting Cdc6 or ORC in mammalian cells does not cause substantial re-replication. Overexpression of Cdt1, on the other hand, can lead to potentially lethal re-replication levels on its own. This response is seen only in cancer cells. [25] Overexpression of E2F family members contributes to an increase in Cdt1 and Cdc6 expression. Loss of p53 regulation in cells can also be observed frequently in cell lines that overexpress Cdt1 or Cdc6. [11]

Endoreduplication

For the special case of cell cycle-regulated DNA replication in which DNA synthesis is uncoupled from cell cycle progression, refer to endoreduplication. Endoreduplication is an important and widespread mechanism in many cell types. It does not adhere to many of the cell cycle checkpoints and damage controls in regularly dividing cells, but it does not result in uncontrolled re-replication. Endoreduplication is a controlled process and occurs to perform a specific cell function. In some cells, it has been proposed that endoreduplication is used as a way to store nucleotides for embryogenesis and germination. In other cases, endoreduplication may be used in cells that are only used for storage of nutrients. Despite its useful functioning in many cells, endoreduplication has also been observed in cancerous cells, and it is not fully understood whether endoreduplication leads to cancerous behavior or whether other mutations lead to endoreduplication. Other mechanisms may be involved in mediating these changes. [26]

Related Research Articles

<span class="mw-page-title-main">Cell cycle</span> Series of events and stages that result in cell division

The cell cycle, or cell-division cycle, is the series of events that take place in a cell that causes it to divide into two daughter cells. These events include the duplication of its DNA and some of its organelles, and subsequently the partitioning of its cytoplasm, chromosomes and other components into two daughter cells in a process called cell division.

<span class="mw-page-title-main">DNA replication</span> Biological process

In molecular biology, DNA replication is the biological process of producing two identical replicas of DNA from one original DNA molecule. DNA replication occurs in all living organisms acting as the most essential part of biological inheritance. This is essential for cell division during growth and repair of damaged tissues, while it also ensures that each of the new cells receives its own copy of the DNA. The cell possesses the distinctive property of division, which makes replication of DNA essential.

<span class="mw-page-title-main">Origin of replication</span> Sequence in a genome

The origin of replication is a particular sequence in a genome at which replication is initiated. Propagation of the genetic material between generations requires timely and accurate duplication of DNA by semiconservative replication prior to cell division to ensure each daughter cell receives the full complement of chromosomes. This can either involve the replication of DNA in living organisms such as prokaryotes and eukaryotes, or that of DNA or RNA in viruses, such as double-stranded RNA viruses. Synthesis of daughter strands starts at discrete sites, termed replication origins, and proceeds in a bidirectional manner until all genomic DNA is replicated. Despite the fundamental nature of these events, organisms have evolved surprisingly divergent strategies that control replication onset. Although the specific replication origin organization structure and recognition varies from species to species, some common characteristics are shared.

<span class="mw-page-title-main">Pre-replication complex</span>

A pre-replication complex (pre-RC) is a protein complex that forms at the origin of replication during the initiation step of DNA replication. Formation of the pre-RC is required for DNA replication to occur. Complete and faithful replication of the genome ensures that each daughter cell will carry the same genetic information as the parent cell. Accordingly, formation of the pre-RC is a very important part of the cell cycle.

G<sub>2</sub> phase Second growth phase in the eukaryotic cell cycle, prior to mitosis

G2 phase, Gap 2 phase, or Growth 2 phase, is the third subphase of interphase in the cell cycle directly preceding mitosis. It follows the successful completion of S phase, during which the cell’s DNA is replicated. G2 phase ends with the onset of prophase, the first phase of mitosis in which the cell’s chromatin condenses into chromosomes.

Endoreduplication is replication of the nuclear genome in the absence of mitosis, which leads to elevated nuclear gene content and polyploidy. Endoreduplication can be understood simply as a variant form of the mitotic cell cycle (G1-S-G2-M) in which mitosis is circumvented entirely, due to modulation of cyclin-dependent kinase (CDK) activity. Examples of endoreduplication characterised in arthropod, mammalian, and plant species suggest that it is a universal developmental mechanism responsible for the differentiation and morphogenesis of cell types that fulfill an array of biological functions. While endoreduplication is often limited to specific cell types in animals, it is considerably more widespread in plants, such that polyploidy can be detected in the majority of plant tissues. Polyploidy and aneuploidy are common phenomena in cancer cells. Given that oncogenesis and endoreduplication likely involve subversion of common cell cycle regulatory mechanisms, a thorough understanding of endoreduplication may provide important insights for cancer biology.

A licensing factor is a protein or complex of proteins that allows an origin of replication to begin DNA replication at that site. Licensing factors primarily occur in eukaryotic cells, since bacteria use simpler systems to initiate replication. However, many archaea use homologues of eukaryotic licensing factors to initiate replication.

Cyclin A is a member of the cyclin family, a group of proteins that function in regulating progression through the cell cycle. The stages that a cell passes through that culminate in its division and replication are collectively known as the cell cycle Since the successful division and replication of a cell is essential for its survival, the cell cycle is tightly regulated by several components to ensure the efficient and error-free progression through the cell cycle. One such regulatory component is cyclin A which plays a role in the regulation of two different cell cycle stages.

<span class="mw-page-title-main">Geminin</span> Nuclear protein inhibiting DNA replication

Geminin, DNA replication inhibitor, also known as GMNN, is a protein in humans encoded by the GMNN gene. A nuclear protein present in most eukaryotes and highly conserved across species, numerous functions have been elucidated for geminin including roles in metazoan cell cycle, cellular proliferation, cell lineage commitment, and neural differentiation. One example of its function is the inhibition of Cdt1.

In molecular biology, origin recognition complex (ORC) is a multi-subunit DNA binding complex that binds in all eukaryotes and archaea in an ATP-dependent manner to origins of replication. The subunits of this complex are encoded by the ORC1, ORC2, ORC3, ORC4, ORC5 and ORC6 genes. ORC is a central component for eukaryotic DNA replication, and remains bound to chromatin at replication origins throughout the cell cycle.

<span class="mw-page-title-main">Eukaryotic DNA replication</span> DNA replication in eukaryotic organisms

Eukaryotic DNA replication is a conserved mechanism that restricts DNA replication to once per cell cycle. Eukaryotic DNA replication of chromosomal DNA is central for the duplication of a cell and is necessary for the maintenance of the eukaryotic genome.

<span class="mw-page-title-main">Minichromosome maintenance</span>

The minichromosome maintenance protein complex (MCM) is a DNA helicase essential for genomic DNA replication. Eukaryotic MCM consists of six gene products, Mcm2–7, which form a heterohexamer. As a critical protein for cell division, MCM is also the target of various checkpoint pathways, such as the S-phase entry and S-phase arrest checkpoints. Both the loading and activation of MCM helicase are strictly regulated and are coupled to cell growth cycles. Deregulation of MCM function has been linked to genomic instability and a variety of carcinomas.

<span class="mw-page-title-main">MCM2</span> Protein-coding gene in the species Homo sapiens

DNA replication licensing factor MCM2 is a protein that in humans is encoded by the MCM2 gene.

<span class="mw-page-title-main">DNA replication factor CDT1</span> Protein-coding gene in the species Homo sapiens

CDT1 is a protein that in humans is encoded by the CDT1 gene. It is a licensing factor that functions to limit DNA from replicating more than once per cell cycle.

<span class="mw-page-title-main">Cell division cycle 7-related protein kinase</span> Protein-coding gene in the species Homo sapiens

Cell division cycle 7-related protein kinase is an enzyme that in humans is encoded by the CDC7 gene. The Cdc7 kinase is involved in regulation of the cell cycle at the point of chromosomal DNA replication. The gene CDC7 appears to be conserved throughout eukaryotic evolution; this means that most eukaryotic cells have the Cdc7 kinase protein.

<span class="mw-page-title-main">Cdc6</span>

Cdc6, or cell division cycle 6, is a protein in eukaryotic cells. It is mainly studied in the budding yeast Saccharomyces cerevisiae. It is an essential regulator of DNA replication and plays important roles in the activation and maintenance of the checkpoint mechanisms in the cell cycle that coordinate S phase and mitosis. It is part of the pre-replicative complex (pre-RC) and is required for loading minichromosome maintenance (MCM) proteins onto the DNA, an essential step in the initiation of DNA synthesis. In addition, it is a member of the family of AAA+ ATPases and highly related to ORC1; both are the same protein in archaea.

<span class="mw-page-title-main">Control of chromosome duplication</span>

In cell biology, eukaryotes possess a regulatory system that ensures that DNA replication occurs only once per cell cycle.

<span class="mw-page-title-main">ORC1</span> Protein-coding gene in the species Homo sapiens

Origin recognition complex subunit 1 is a protein that in humans is encoded by the ORC1 gene. It is closely related to CDC6, and both are the same protein in archaea.

Anindya Dutta is an Indian-born American biochemist and cancer researcher, a Chair of the Department of Genetics at the University of Alabama at Birmingham School of Medicine since 2021, who has served as Chair of the Department of Biochemistry and Molecular Genetics at the University of Virginia School of Medicine in 2011–2021. Dutta's research has focused on the mammalian cell cycle with an emphasis on DNA replication and repair and on noncoding RNAs. He is particularly interested in how de-regulation of these processes promote cancer progression. For his accomplishments he has been elected a Fellow of the American Association for the Advancement of Science, received the Ranbaxy Award in Biomedical Sciences, the Outstanding Investigator Award from the American Society for Investigative Pathology, the Distinguished Scientist Award from the University of Virginia and the Mark Brothers Award from the Indiana University School of Medicine.

Julian Blow is a molecular biologist, Professor of Chromosome Maintenance, and also the Dean of the School of Life Sciences, University of Dundee, Scotland.

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