# DNA Replication Before Mitosis: Why It Must Happen ## Introduction to DNA Replication and Mitosis DNA replication is the process by which a cell duplicates its entire genome, producing two identical copies of each chromosome. Mitosis is the subsequent division of the nucleus that distributes these duplicated chromosomes equally into two daughter cells. The temporal separation of these two events—replication first, then division—is not arbitrary; it is a fundamental requirement for genetic continuity across cell generations. Every time a cell divides, it must ensure that each daughter cell receives a complete and accurate copy of the genetic information. This requires that the DNA be duplicated *before* the chromosomes are segregated. If a cell attempted mitosis without prior replication, each daughter cell would receive only half the genetic material, a condition incompatible with viability in virtually all organisms. The relationship between replication and mitosis is governed by the cell cycle, a tightly regulated sequence of events that ensures replication is completed and verified before chromosome segregation begins. Understanding why [DNA Replication Occur in S Phase](/knowledge/molecular-biology/dna-replication-occur-in-s-phase) is central to understanding how cells maintain genomic stability across generations. ### The Cell Cycle Overview The eukaryotic cell cycle is divided into four phases: G1 (gap 1), S (synthesis), G2 (gap 2), and M (mitosis). G1, S, and G2 collectively constitute interphase, the period between mitotic divisions. During G1, the cell grows and prepares for DNA synthesis. The S phase is when DNA replication occurs. During G2, the cell verifies that replication is complete and repairs any damage before entering mitosis. The M phase encompasses both mitosis (nuclear division) and cytokinesis (cytoplasmic division). The duration of these phases varies by cell type. A typical mammalian cell in culture has a cell cycle of approximately 24 hours: G1 lasts about 11 hours, S phase about 8 hours, G2 about 4 hours, and M phase about 1 hour. The S phase is therefore a substantial commitment of cellular resources and time, reflecting the complexity of accurately duplicating the genome. ### Why Duplication is Essential The fundamental purpose of DNA replication before mitosis is to maintain the chromosome number and genetic content of the species. A human somatic cell contains 46 chromosomes (23 pairs). After replication, it temporarily contains 92 chromosomes (46 pairs of sister chromatids). Mitosis separates these sister chromatids, ensuring that each daughter cell receives exactly 46 chromosomes. This process follows the principle of [Semiconservative Replication](/knowledge/molecular-biology/semiconservative-replication), whereby each new DNA molecule contains one original strand and one newly synthesized strand. This mechanism, demonstrated by Meselson and Stahl in 1958 using isotopic labeling of *E. coli* DNA, ensures that the nucleotide sequence is faithfully copied from the parental template. Without prior replication, mitosis would halve the chromosome number with each division. After one division, a cell would have 23 chromosomes; after two, approximately 11 or 12; and so on. Such progressive loss of genetic information would rapidly lead to cell death. The cell cycle has therefore evolved to enforce a strict order: replication must be completed before chromosome segregation can begin. ## The Cell Cycle: Where Replication Fits The placement of DNA replication in the S phase, between G1 and G2, is a critical feature of the cell cycle. This arrangement provides temporal separation between the decision to divide, the act of genome duplication, and the execution of chromosome segregation. ### Phases of Interphase Interphase comprises G1, S, and G2. Each phase has distinct functions and regulatory features: **G1 Phase:** The cell grows, synthesizes RNA and proteins, and monitors its environment. During G1, the cell decides whether to commit to another round of division. If conditions are unfavorable, the cell may exit the cycle into G0, a quiescent state. The restriction point in mammalian cells (START in yeast) marks the commitment point beyond which the cell is irreversibly destined for division. **S Phase:** DNA replication initiates at multiple origins throughout the genome. The entire genome is duplicated exactly once. Histone proteins are synthesized in coordination with DNA synthesis to package the newly replicated DNA into chromatin. **G2 Phase:** The cell continues to grow and synthesizes proteins required for mitosis. Critically, the G2 phase provides a window for the cell to verify that replication is complete and that the DNA is undamaged before committing to chromosome segregation. The transition from G1 to S is regulated by [cyclin-dependent kinases](/knowledge/molecular-biology/cyclin-dependent-kinase) (CDKs). Cyclin E-CDK2 activity drives the G1/S transition, while cyclin A-CDK2 is required during S phase. The activity of these kinases is controlled by cyclin synthesis and degradation, CDK inhibitors (such as p21 and p27), and phosphorylation events. ### The G1/S Checkpoint The G1/S checkpoint determines whether the cell proceeds with DNA replication. This checkpoint assesses cell size, nutrient availability, growth factor signaling, and DNA damage. Key players include the tumor suppressor p53 and the retinoblastoma protein (Rb). When DNA damage is detected, the kinase ATM (ataxia-telangiectasia mutated) or ATR (ATM- and Rad3-related) phosphorylates and activates Chk1 or Chk2 kinases. These kinases phosphorylate p53, stabilizing it and increasing its transcriptional activity. p53 induces expression of p21, a CDK inhibitor that blocks cyclin E-CDK2 activity, thereby preventing entry into S phase. The G1/S checkpoint is also the point where the decision to replicate is coupled to the availability of replication origins. In G1, the origin recognition complex (ORC) binds to [Replication Origin](/knowledge/molecular-biology/replication-origin) sites throughout the genome. Cdc6 and Cdt1 then load the minichromosome maintenance (MCM) helicase complex, forming the pre-replicative complex (pre-RC). This licensing process ensures that each origin is competent to fire during S phase. ### G2 Checkpoint and Readiness for Mitosis The G2/M checkpoint ensures that DNA replication is complete and that the genome is not damaged before mitosis begins. This checkpoint monitors: - Completion of DNA replication - DNA damage status - Proper chromosome condensation The key regulator is cyclin B-CDK1 (also called maturation-promoting factor, MPF). Cyclin B accumulates during G2, but CDK1 remains inactive until dephosphorylated by the phosphatase Cdc25. DNA damage activates Chk1/Chk2, which phosphorylate and inhibit Cdc25, preventing CDK1 activation and blocking entry into mitosis. If replication is incomplete, the ATR kinase is activated by persistent single-stranded DNA at unreplicated regions. ATR activates Chk1, which similarly inhibits Cdc25 and maintains CDK1 in its inactive, phosphorylated state. This ensures that mitosis cannot begin until replication has finished. ## Molecular Mechanism of DNA Replication DNA replication is a highly coordinated process involving dozens of proteins. The fundamental steps—initiation, elongation, and termination—are conserved from bacteria to humans, though eukaryotic replication is more complex due to the larger genome and chromatin structure. ### Initiation at Origins Replication begins at specific DNA sequences called origins of replication. In *Saccharomyces cerevisiae* (budding yeast), origins are defined by the autonomously replicating sequence (ARS) consensus sequence. In higher eukaryotes, origins are less well-defined by sequence and are instead influenced by chromatin structure, transcriptional activity, and DNA topology. The initiation process involves ordered assembly of proteins: 1. **Origin recognition:** The origin recognition complex (ORC), a six-subunit ATPase, binds to the origin DNA throughout the cell cycle. 2. **Licensing:** During G1, Cdc6 and Cdt1 bind to ORC and load the MCM2-7 helicase complex, forming the pre-replicative complex (pre-RC). The MCM2-7 complex is loaded as a double hexamer encircling the DNA. 3. **Activation:** At the G1/S transition, CDK and Dbf4-dependent kinase (DDK) phosphorylate components of the pre-RC. This triggers recruitment of additional factors: Cdc45, the GINS complex, and the replicative DNA polymerases. 4. **Unwinding:** The MCM2-7 helicase unwinds the DNA duplex, creating a [Replication Fork Definition](/knowledge/molecular-biology/replication-fork-definition) —the Y-shaped region where active synthesis occurs. The transition from a licensed origin to an active replication fork is called origin firing. In eukaryotes, origins fire throughout S phase according to a temporal program. Early-firing origins are typically in euchromatic, gene-rich regions, while late-firing origins are in heterochromatic regions. The [Replication Fork Bubble](/knowledge/molecular-biology/replication-fork-bubble) formed by bidirectional unwinding from a single origin is visible by electron microscopy. ### Elongation by DNA Polymerases DNA polymerases synthesize new DNA in the 5' to 3' direction, adding nucleotides to the 3'-hydroxyl group of the growing strand. In eukaryotes, three replicative polymerases are involved: - **DNA polymerase α (Pol α):** A primase-polymerase complex that synthesizes short RNA-DNA primers (~10 RNA nucleotides + ~20 DNA nucleotides) at the start of each Okazaki fragment. - **DNA polymerase δ (Pol δ):** The lagging strand polymerase, which extends Okazaki fragments. - **DNA polymerase ε (Pol ε):** The leading strand polymerase, which synthesizes DNA continuously. The replication fork is asymmetric. The leading strand is synthesized continuously in the same direction as fork movement. The lagging strand is synthesized discontinuously as Okazaki fragments, each initiated by a new primer. The processivity of DNA polymerases is enhanced by the sliding clamp PCNA (proliferating cell nuclear antigen), which encircles the DNA and tethers the polymerase to the template. PCNA is loaded onto DNA by the clamp loader RFC (replication factor C). This interaction increases polymerase processivity from approximately 10 nucleotides to thousands of nucleotides per binding event. ### Okazaki Fragments and Ligation Okazaki fragments on the lagging strand are typically 100-200 nucleotides long in eukaryotes. Each fragment requires: 1. **Primer synthesis:** Pol α synthesizes an RNA-DNA primer. 2. **Polymerase switching:** RFC displaces Pol α and loads PCNA, which recruits Pol δ. 3. **Extension:** Pol δ extends the fragment until it reaches the RNA primer of the preceding fragment. 4. **Primer removal:** The RNA primers are removed by RNase H and the flap endonuclease FEN1. RNase H cleaves the RNA portion, while FEN1 removes the resulting 5' flap structure. 5. **Ligation:** DNA ligase I seals the nick between adjacent fragments, creating a continuous DNA strand. The coordination of leading and lagging strand synthesis requires the replisome, a multiprotein complex that includes the MCM helicase, polymerases, PCNA, RFC, and accessory factors. The replisome is remarkably processive, capable of replicating the entire 250 Mb human genome in approximately 8 hours. ## Ensuring Accuracy: Proofreading and Repair DNA replication is remarkably accurate, with an error rate of approximately 1 in 10⁹ to 10¹⁰ nucleotides. This fidelity arises from three mechanisms: base selection by the polymerase, proofreading, and post-replicative mismatch repair. ### 3' to 5' Exonuclease Activity DNA polymerases δ and ε possess intrinsic 3' to 5' exonuclease activity that removes mismatched nucleotides immediately after incorporation. When a polymerase incorporates an incorrect nucleotide, the mispaired 3' terminus cannot be extended efficiently. The polymerase pauses and transfers the primer terminus to the exonuclease active site, where the mismatched nucleotide is removed. The primer is then transferred back to the polymerase active site for continued synthesis. This proofreading activity reduces the error rate from approximately 10⁻⁵ (base selection alone) to approximately 10⁻⁷ (base selection plus proofreading). The exonuclease active site is structurally distinct from the polymerase active site, and the transfer between the two requires a conformational change in the enzyme. ### Mismatch Repair Pathway Mismatch repair (MMR) corrects errors that escape proofreading. This pathway recognizes and repairs base-base mismatches and small insertion-deletion loops that arise during replication. In humans, the key MMR proteins are: - **MSH2-MSH6 (MutSα):** Recognizes base-base mismatches and small loops. - **MSH2-MSH3 (MutSβ):** Recognizes larger insertion-deletion loops. - **MLH1-PMS2 (MutLα):** Endonuclease that introduces nicks in the newly synthesized strand. - **EXO1:** Exonuclease that degrades the error-containing strand. - **PCNA and RFC:** Coordinate MMR with replication. The MMR system must distinguish the newly synthesized strand from the template strand. In eukaryotes, this discrimination is achieved through the presence of nicks in the newly synthesized strand, which are transiently present during Okazaki fragment processing. The MutLα endonuclease introduces additional nicks, and EXO1 degrades the strand from the nick toward the mismatch. DNA polymerase δ then resynthesizes the gap, and DNA ligase seals the nick. Defects in MMR cause Lynch syndrome (hereditary non-polyposis colorectal cancer), characterized by microsatellite instability and a greatly increased risk of colorectal, endometrial, and other cancers. ## Chromosome Structure and Sister Chromatids The products of DNA replication—two identical DNA molecules—must be organized and segregated with precision during mitosis. This requires the formation of sister chromatids held together by cohesin complexes. ### Cohesin and Chromatid Cohesion Cohesin is a ring-shaped protein complex composed of four subunits: SMC1, SMC3, SCC1 (also called RAD21), and SCC3 (also called SA1 or SA2). The cohesin ring is loaded onto chromatin during G1 and establishes cohesion between sister chromatids during S phase as replication forks pass through. The cohesin ring topologically embraces both sister chromatids, holding them together from S phase until mitosis. This cohesion is essential for: - **Biorientation:** Sister chromatids must attach to microtubules from opposite spindle poles. Cohesion resists the pulling forces of microtubules, generating tension that stabilizes correct attachments. - **Error correction:** Improper attachments (both sister chromatids attached to the same pole) are destabilized by the absence of tension, allowing correction. - **Checkpoint signaling:** The tension generated by cohesion at kinetochores silences the spindle assembly checkpoint, allowing anaphase to proceed. At the metaphase-to-anaphase transition, the enzyme separase cleaves SCC1, opening the cohesin ring and allowing sister chromatids to separate. Separase is activated by the anaphase-promoting complex/cyclosome (APC/C), which ubiquitinates and degrades securin, the separase inhibitor. ### Centromere and Kinetochore Assembly The centromere is the specialized chromosomal region where the kinetochore assembles. In humans, centromeres are defined by the presence of the histone H3 variant CENP-A, which replaces conventional H3 in centromeric nucleosomes. CENP-A provides the epigenetic mark that specifies centromere identity and directs kinetochore assembly. The kinetochore is a large protein complex (over 100 proteins) that connects centromeric chromatin to spindle microtubules. Key components include: - **Constitutive centromere-associated network (CCAN):** Proteins that bind CENP-A-containing chromatin. - **KMN network:** The Knl1-Mis12-Ndc80 complex that directly binds microtubules. - **Spindle assembly checkpoint proteins:** Mad1, Mad2, Bub1, BubR1, and Mps1, which monitor microtubule attachment. Each sister chromatid has its own kinetochore, oriented in opposite directions. This geometry ensures that sister chromatids attach to microtubules from opposite spindle poles, enabling their segregation to opposite daughter cells. ## Consequences of Replication Failure or Errors Failure to replicate DNA before mitosis, or errors during replication, have severe consequences for genomic stability and cell viability. ### Cell Cycle Checkpoint Activation The [cell cycle checkpoints](/knowledge/bioinformatics/cell-cycle-checkpoints-a-decision-framework-for-identifying-phase-specific-defects) are designed to prevent mitosis when replication is incomplete or damaged. The primary mechanism involves ATR, which is activated by single-stranded DNA at stalled replication forks. ATR phosphorylates Chk1, which in turn: - Inhibits Cdc25 phosphatases, preventing CDK1 activation. - Promotes degradation of cyclin B. - Maintains the G2/M checkpoint. If the checkpoint is functional, cells with incomplete replication arrest in G2 and do not enter mitosis. However, if the checkpoint is defective (as in many cancer cells), cells may enter mitosis with unreplicated DNA, leading to catastrophic chromosome segregation. ### Genomic Instability and Disease When cells enter mitosis with incompletely replicated DNA, the consequences include: **Aneuploidy:** The unequal distribution of chromosomes to daughter cells. This occurs when unreplicated regions fail to form sister chromatids, leading to missegregation. Aneuploidy is a hallmark of cancer and is frequently caused by defects in replication or checkpoint function. **Chromosome breaks and rearrangements:** Unreplicated DNA is fragile and prone to breakage during mitosis. The resulting double-strand breaks can lead to deletions, duplications, and translocations. **Replication stress:** Conditions that slow or stall replication forks, such as nucleotide depletion or DNA damage, cause replication stress. This is associated with activation of the DNA damage response and can lead to fork collapse and genome instability. **Apoptosis or senescence:** Cells that detect severe replication defects may undergo programmed cell death or enter permanent cell cycle arrest. The link between replication errors and cancer is well established. Mutations in replication genes, including those encoding DNA polymerases, MCM helicases, and MMR proteins, predispose to cancer. For example, germline mutations in *POLE* and *POLD1* (encoding the catalytic subunits of polymerases ε and δ) cause an inherited predisposition to colorectal cancer, characterized by an ultramutated phenotype. ## Experimental Methods to Study Replication Timing Several experimental approaches allow researchers to visualize and quantify DNA replication and its timing within the cell cycle. ### BrdU Incorporation Assay Bromodeoxyuridine (BrdU) is a thymidine analog that is incorporated into newly synthesized DNA during S phase. Cells are incubated with BrdU, then fixed and stained with an anti-BrdU antibody conjugated to a fluorophore. This allows detection of cells that have undergone replication. The assay can be combined with flow cytometry or microscopy to determine: - The fraction of cells in S phase. - The timing of replication initiation. - The spatial distribution of replication within the nucleus. For pulse-chase experiments, cells are exposed to BrdU for a short period (pulse), then washed and incubated in normal medium (chase). This reveals which cells were in S phase during the pulse and allows tracking of their progression through the cell cycle. ### FACS Analysis of Cell Cycle Fluorescence-activated cell sorting (FACS) analysis measures DNA content per cell. Cells are stained with a DNA-binding dye such as propidium iodide or Hoechst 33342, and the fluorescence intensity is measured. Cells in G1 have a 2N DNA content, cells in G2/M have a 4N content, and cells in S phase have intermediate values. FACS analysis provides a quantitative snapshot of cell cycle distribution. When combined with BrdU labeling, it can distinguish cells in different phases of S phase and measure the rate of replication progression. ### Single-Molecule Analysis DNA combing and DNA fiber analysis allow visualization of replication at the single-molecule level. In DNA combing, genomic DNA is stretched on a glass surface and labeled with fluorescent nucleotides (e.g., CIdU and IdU) during replication. The resulting patterns reveal: - Replication origin positions. - Fork direction and speed. - Origin firing efficiency. - [Replication fork stalling](/knowledge/molecular-biology/replication-fork-stalling). This technique has revealed that [replication fork speed](/knowledge/molecular-biology/replication-fork-speed) in human cells is approximately 1-2 kb per minute, and that origins are spaced approximately 50-100 kb apart. [Replication Fork Stalling](/knowledge/molecular-biology/replication-fork-stalling) can be detected as shortened labeled tracks or asymmetric fork progression. ## Common Misconceptions and Study Pitfalls Students frequently encounter several conceptual difficulties when learning about DNA replication and mitosis. ### Replication is Not Part of Mitosis A common error is to consider DNA replication as a step within mitosis. In fact, replication occurs during S phase, which is part of interphase, not mitosis. Mitosis (M phase) is the period of chromosome condensation, alignment, and segregation. The distinction is critical: replication must be completed before mitosis begins, and the two processes are separated by the G2 phase. ### S Phase is Not the Only Time of DNA Synthesis While the bulk of genomic DNA is replicated during S phase, some DNA synthesis occurs outside S phase. Mitochondrial DNA replication occurs throughout the cell cycle. Additionally, DNA repair synthesis (such as [nucleotide excision repair](/knowledge/molecular-biology/nucleotide-excision-repair) and [base excision repair](/knowledge/molecular-biology/base-excision-repair)) can occur at any time. However, these are not part of genome duplication and do not contribute to sister chromatid formation. ### Origin Firing is Regulated Not all origins fire simultaneously at the start of S phase. Origin firing follows a temporal program, with some origins firing early and others late. This regulation ensures that the entire genome is replicated exactly once. If an origin fires in G1 (before licensing is complete) or if a licensed origin fails to fire in S phase, replication errors result. The mechanism preventing re-replication involves: - CDK-dependent phosphorylation of Cdc6, targeting it for degradation. - CDK-dependent phosphorylation of Cdt1, promoting its degradation. - Nuclear export of Cdt1. - Geminin, a protein that binds and inhibits Cdt1 during S, G2, and M phases. These redundant mechanisms ensure that origins are licensed only once per cell cycle. ## Summary: The Critical Link Between Replication and Mitosis DNA replication before mitosis is a non-negotiable requirement for genetic stability. The cell cycle enforces this order through: 1. **Temporal separation:** Replication occurs in S phase, mitosis in M phase, separated by G2. 2. **Checkpoint control:** The G1/S and G2/M checkpoints ensure replication is complete and accurate before mitosis begins. 3. **Molecular mechanisms:** DNA polymerases, proofreading, and mismatch repair ensure replication fidelity. 4. **Chromosome structure:** Sister chromatids, held together by cohesin, provide the physical basis for equal segregation. 5. **Failure consequences:** Incomplete or erroneous replication leads to aneuploidy, genomic instability, and disease. The [Semi Conservative Replication](/knowledge/molecular-biology/semi-conservative-replication) mechanism ensures that each daughter cell receives one parental strand and one newly synthesized strand, preserving the genetic information across generations. The [Replication Fork Diagram](/knowledge/molecular-biology/replication-fork-diagram) illustrates the coordinated action of helicases, polymerases, and accessory proteins at the site of active DNA synthesis. Understanding why DNA replication must occur before mitosis is fundamental to understanding cell biology, genetics, and the [molecular basis of cancer](/knowledge/molecular-biology/molecular-basis-of-cancer). The regulatory mechanisms that couple replication to mitosis are among the most elegant and critical control systems in biology. ## Frequently Asked Questions ### Does DNA replication occur before mitosis? Yes. DNA replication occurs during the S phase of interphase, which precedes mitosis. The G2 phase separates S phase from mitosis, providing time for the cell to verify that replication is complete and accurate before chromosome segregation begins. ### Why does DNA replication occur before mitosis? Replication must occur before mitosis so that each daughter cell receives a complete copy of the genome. During mitosis, sister chromatids are separated and distributed to daughter cells. If replication had not occurred, each daughter cell would receive only half the genetic material, which is incompatible with viability. ### What happens if DNA replication does not occur before mitosis? If a cell enters mitosis without completing replication, the G2/M checkpoint should normally prevent this. If the checkpoint is defective, the cell may attempt to segregate unreplicated chromosomes, leading to chromosome breaks, aneuploidy, and genomic instability. Such events are frequently observed in cancer cells. ### Is DNA replication part of mitosis? No. DNA replication occurs during S phase, which is part of interphase, not mitosis. Mitosis (M phase) is the process of chromosome condensation, alignment on the metaphase plate, and segregation to daughter cells. Replication and mitosis are separated by the G2 phase. ### How is DNA replication regulated before mitosis? DNA replication is regulated at multiple levels: origin licensing in G1, origin firing during S phase, and checkpoint control at the G1/S and G2/M transitions. CDKs and DDK phosphorylate replication proteins to trigger origin firing, while checkpoint kinases (ATM, ATR, Chk1, Chk2) monitor replication completion and DNA damage. ### What is the role of sister chromatids in mitosis? Sister chromatids are the two identical copies of a chromosome produced by DNA replication. They are held together by cohesin complexes and must be segregated to opposite daughter cells during mitosis. Sister chromatid cohesion is essential for proper microtubule attachment and chromosome alignment. ### Can DNA replication occur during mitosis? No. DNA replication is restricted to S phase. The mitotic chromatin is condensed and the replication machinery is inactivated. CDK activity during mitosis promotes the degradation of replication licensing factors, preventing any attempt at replication. Additionally, the nuclear envelope breaks down during mitosis, and replication requires an intact nucleus. ## Key Takeaways - DNA replication occurs during S phase of interphase, strictly before mitosis, and is separated from mitosis by the G2 phase. - The G1/S and G2/M checkpoints ensure that replication is complete and accurate before chromosome segregation begins. - DNA polymerases δ and ε synthesize DNA with high fidelity through base selection, 3' to 5' proofreading, and mismatch repair. - Sister chromatids, held together by cohesin, are the physical products of replication that enable equal chromosome segregation. - Failure to replicate before mitosis causes aneuploidy, chromosome breaks, and genomic instability, which are hallmarks of cancer. - Origin licensing and firing are tightly regulated to ensure that the genome is replicated exactly once per cell cycle. - Experimental methods including BrdU incorporation, FACS analysis, and DNA combing allow direct visualization of replication timing and dynamics. ## Further Reading - Gelot C, Magdalou I, Lopez BS. *Replication stress in Mammalian cells and its consequences for mitosis*. Genes. 2015. [PubMed 26010955](https://doi.org/10.3390/genes6020267) - Kurniawan F et al. *Phosphorylation of Orc6 During Mitosis Regulates DNA Replication and Ribosome Biogenesis*. [Molecular and cellular biology](/blog/careers/molecular-and-cellular-biology). 2024. [PubMed 38867464](https://doi.org/10.1080/10985549.2024.2356880) - Wilson TE et al. *Replication stress induces POLQ-mediated structural variant formation throughout common fragile sites after entry into mitosis*. Nature communications. 2024. [PubMed 39505880](https://doi.org/10.1038/s41467-024-53917-8) - Torres-Rosell J et al. *Anaphase onset before complete DNA replication with intact checkpoint responses*. Science (New York, N.Y.). 2007. [PubMed 17347440](https://doi.org/10.1126/science.1134025) ## Related Clinical & Scientific Guides * [MAPK Pathway: Mechanism, Function, and Clinical Relevance](/knowledge/molecular-biology/mapk-pathway) * [Mammalian Cell Culture Bioreactors: A Practical Guide](/knowledge/molecular-biology/mammalian-cell-culture-bioreactor) * [Nucleotide Formation: Biosynthesis and Assembly of DNA/RNA Building Blocks](/knowledge/molecular-biology/nucleotide-formation)