Replication Fork Stalling: Causes, Consequences, and Mechanisms

By Dr. Zubair Khalid, DVM, MS, PhD · 2026-08-11

Introduction to Replication Fork Stalling

DNA replication is a remarkably processive and accurate process, yet it is constantly challenged by obstacles that impede the progression of replication forks. Replication fork stalling refers to the slowing or complete halting of the replication machinery when it encounters a barrier on the DNA template. This phenomenon is not merely an occasional accident; it is a frequent event that every proliferating cell must manage. In human cells, it is estimated that each replication fork encounters hundreds of potential obstacles per cell cycle, making fork stalling a routine challenge rather than a rare catastrophe.

The significance of replication fork stalling extends far beyond the immediate pause in DNA synthesis. When a fork stalls, it generates stretches of single-stranded DNA (ssDNA) that are vulnerable to damage and serve as signals that activate the DNA damage response. If the stall is not resolved promptly, the fork can collapse into a double-strand break (DSB), a highly toxic lesion that can trigger chromosomal rearrangements and genomic instability. The term replication stress encompasses the broader cellular state characterized by slowed or stalled fork progression, ssDNA accumulation, and the activation of checkpoint pathways. Understanding replication fork stalling is therefore central to comprehending how cells maintain genome integrity and how defects in these processes contribute to cancer and premature aging.

The Replication Fork and Its Normal Progression

To understand what goes wrong when a fork stalls, one must first appreciate the architecture of the normal replication fork. The replication fork is the Y-shaped region where the parental DNA duplex is unwound and two new daughter strands are synthesized. A detailed visual representation of this structure can be found in the Replication Fork Diagram, while the Replication Fork Definition provides a concise overview of the terminology.

Replisome Components

The replication fork is operated by a multi-protein machine called the replisome. In eukaryotic cells, the core replisome comprises the following key components:

• CMG helicase: The Cdc45-MCM2-7-GINS complex is the replicative helicase that unwinds the parental DNA duplex. The MCM2-7 hexamer forms the motor core, which translocates along the leading-strand template in a 3′ to 5′ direction, using ATP hydrolysis to drive unwinding.
• DNA polymerases: DNA polymerase ε (Pol ε) synthesizes the leading strand, while DNA polymerase δ (Pol δ) primarily synthesizes the lagging strand. Both are B-family polymerases with high processivity and proofreading activity.
• PCNA: Proliferating cell nuclear antigen is a sliding clamp that encircles DNA and tethers the polymerases to their templates, dramatically increasing their processivity.
• RPA: Replication protein A is a heterotrimeric ssDNA-binding protein that coats and stabilizes the single-stranded regions generated during unwinding and synthesis.
• Primase: DNA polymerase α-primase synthesizes the short RNA-DNA primers required to initiate each Okazaki fragment on the lagging strand.
• RFC: Replication factor C is the clamp loader that deposits PCNA onto primer-template junctions.

Leading and Lagging Strand Synthesis

DNA polymerases can only synthesize DNA in the 5′ to 3′ direction, which imposes an asymmetry on the replication fork. The leading strand is synthesized continuously in the same direction as fork movement, requiring only a single primer at the origin. The lagging strand is synthesized discontinuously in the opposite direction, producing short Okazaki fragments that are each primed separately and later joined by DNA ligase I.

The helicase unwinds the duplex ahead of the polymerases, creating a ssDNA template for both strands. On the leading strand, Pol ε synthesizes DNA processively, coupled directly to helicase movement. On the lagging strand, the template is extruded as a loop, allowing Pol δ to synthesize Okazaki fragments in the same physical direction as fork movement despite the opposite polarity of the template. This coordination ensures that both strands are synthesized at approximately the same rate, typically 1–2 kb per minute in human cells, although the Replication Fork Speed varies across organisms and cell types.

Causes of Replication Fork Stalling

A wide variety of obstacles can impede replication fork progression. These causes can be broadly categorized into endogenous sources, which arise from normal cellular metabolism, and exogenous sources, which result from environmental exposures.

DNA Lesions and Damage

The most common cause of fork stalling is the presence of DNA lesions on the template. The leading-strand polymerase is particularly sensitive to template damage because it must read every nucleotide; a single bulky adduct can halt synthesis entirely. Key lesions that cause stalling include:

• Bulky adducts: Compounds such as benzo[a]pyrene diol epoxide and cisplatin crosslinks distort the DNA helix and physically block polymerase progression.
• Pyrimidine dimers: UV radiation induces cyclobutane pyrimidine dimers (CPDs) and 6-4 photoproducts, which are potent blocks to replicative polymerases.
• Abasic sites: Spontaneous depurination generates abasic (AP) sites that lack a coding base. These sites are non-instructional and stall polymerases.
• DNA crosslinks: Interstrand crosslinks (ICLs) covalently link the two strands of the duplex, preventing strand separation and completely blocking fork progression.
• Oxidized bases: 8-oxoguanine is a common oxidative lesion that can cause misincorporation and stalling, particularly when present on the leading-strand template.

DNA Secondary Structures

Even undamaged DNA can present obstacles when it adopts non-B-form secondary structures. These structures are particularly problematic in regions of repetitive DNA:

• Hairpins and cruciforms: Inverted repeats can form hairpin structures on single-stranded DNA, particularly on the lagging strand template, which is transiently single-stranded during Okazaki fragment synthesis.
• G-quadruplexes (G4s): Guanine-rich sequences can fold into four-stranded structures stabilized by Hoogsteen base pairing. G4 motifs are enriched in telomeres, promoters, and oncogene regulatory regions, and they are potent blocks to both helicase and polymerase activity.
• Triple helices (H-DNA): Homopurine-homopyrimidine tracts can form intramolecular triple helices that impede fork progression.
• R-loops: These three-stranded structures consist of an RNA-DNA hybrid and a displaced ssDNA strand. R-loops form co-transcriptionally and are increasingly recognized as major sources of replication stress, particularly in GC-rich and highly transcribed regions.

Protein-DNA Barriers

The replisome must also contend with proteins that are tightly bound to DNA. While the helicase can displace many DNA-binding proteins, some are too stable to be removed:

• Transcription complexes: A head-on collision between a replication fork and an RNA polymerase transcribing in the opposite direction is a potent stall signal. Even co-directional collisions can cause pauses, particularly at highly transcribed genes.
• Topoisomerase cleavage complexes: Topoisomerase I and II form transient covalent linkages with DNA. When these enzymes are trapped on DNA by drugs such as camptothecin or etoposide, they create stable protein-DNA adducts that block fork progression.
• DNA repair intermediates: Partially processed repair intermediates, such as those formed during nucleotide excision repair or mismatch repair, can transiently block forks.
• Centromeric and telomeric proteins: Specialized chromatin structures at centromeres and telomeres, including the CENP-A nucleosome and shelterin complexes, present natural barriers to fork progression.

Nucleotide Depletion

The replisome requires a continuous supply of deoxyribonucleotide triphosphates (dNTPs) to sustain DNA synthesis. When dNTP pools are depleted, polymerase activity slows or halts. This can occur through:

• Hydroxyurea (HU) treatment: HU inhibits ribonucleotide reductase, the enzyme that converts ribonucleotides to deoxyribonucleotides, causing a rapid depletion of dNTP pools.
• Deregulated dNTP metabolism: Mutations in genes encoding ribonucleotide reductase subunits or dNTP salvage enzymes can cause chronic replication stress.
• Metabolic stress: Conditions that limit nucleotide biosynthesis, such as nutrient deprivation or hypoxia, can reduce dNTP pools.

Molecular Mechanisms of Fork Stalling

When a replication fork encounters an obstacle, a series of molecular events unfolds that distinguishes a transient pause from a catastrophic collapse.

Helicase-Polymerase Uncoupling

The key initiating event in fork stalling is the uncoupling of helicase and polymerase activities. Under normal conditions, the CMG helicase and the leading-strand polymerase move in a coordinated fashion. When the leading-strand polymerase encounters a blocking lesion, it halts. However, the helicase continues to unwind the duplex for a short period before it too stops. This creates a region of ssDNA on the leading-strand template that is not being replicated.

The extent of uncoupling depends on the nature of the obstacle. For a bulky adduct that blocks the polymerase but not the helicase, the helicase may continue for hundreds of base pairs, generating a long stretch of ssDNA. In contrast, an interstrand crosslink blocks helicase unwinding directly, causing minimal uncoupling but complete fork arrest.

RPA Coating and Checkpoint Activation

The ssDNA generated by helicase-polymerase uncoupling is immediately bound by RPA. RPA coating serves two critical functions. First, it protects the vulnerable ssDNA from nucleases and prevents the formation of secondary structures. Second, it serves as a signal that recruits the ATR kinase to the stalled fork.

The recruitment of ATR is a multi-step process. RPA-coated ssDNA recruits the ATR-interacting protein (ATRIP), which brings ATR to the fork. Simultaneously, the RAD17-RFC complex loads the 9-1-1 clamp (RAD9-HUS1-RAD1) onto the junction between ssDNA and double-stranded DNA (dsDNA) at the fork. The 9-1-1 clamp then recruits the TopBP1 activator, which stimulates ATR kinase activity. Once activated, ATR phosphorylates a wide range of substrates, including the effector kinase CHK1, initiating the replication checkpoint response.

Cellular Responses to Fork Stalling

The cellular response to fork stalling is coordinated by the DNA damage response (DDR) and the replication checkpoint. These pathways are essential for stabilizing stalled forks and preventing their collapse into DSBs.

ATR/CHK1 Pathway

The ATR/CHK1 pathway is the primary signaling cascade activated by replication fork stalling. Upon recruitment to RPA-coated ssDNA, ATR phosphorylates and activates CHK1 at serine 317 and serine 345. Activated CHK1 then phosphorylates a variety of downstream effectors that orchestrate the cellular response:

• Cell cycle arrest: CHK1 phosphorylates CDC25A, targeting it for ubiquitin-mediated degradation. This prevents the activation of CDK2, blocking the G1/S and G2/M transitions and halting cell cycle progression.
• Inhibition of origin firing: CHK1 phosphorylates components of the pre-replication complex, including CDC45 and Treslin, preventing the firing of dormant origins. This ensures that cells do not initiate new replication forks while existing forks are stalled.
• Stimulation of dNTP synthesis: CHK1 phosphorylates and inactivates the WEE1 kinase, which in turn promotes the activity of ribonucleotide reductase, increasing dNTP pools to support replication restart.

Fork Stabilization and Remodeling

In addition to signaling, the checkpoint response physically stabilizes stalled forks. Key mechanisms include:

• Protection of nascent DNA: The RAD51 recombinase loads onto stalled forks and protects the nascent DNA strands from degradation by nucleases such as MRE11, EXO1, and DNA2. This RAD51-mediated protection is critical for fork stability and is regulated by BRCA1 and BRCA2.
• Inhibition of fork reversal: The SMARCAL1 and ZRANB3 translocases can promote fork reversal, a remodeling process that creates a four-way junction. The checkpoint kinase ATR phosphorylates SMARCAL1 to limit excessive fork reversal, which can otherwise lead to fork collapse.
• Recruitment of repair factors: The checkpoint response recruits DNA repair proteins to the stalled fork, including Fanconi anemia pathway components and homologous recombination factors, which are poised to act if the fork cannot be restarted.

Fork Restart and Repair Mechanisms

Once a fork has stalled, the cell must restart DNA synthesis to complete replication. Several mechanisms exist to achieve this, depending on the nature of the obstacle and the extent of fork damage.

Homologous Recombination

Homologous recombination (HR) is the primary pathway for restarting forks that have collapsed or undergone extensive remodeling. The process involves:

1. Resection: The DSB or regressed fork end is resected by the MRE11-RAD50-NBS1 (MRN) complex, EXO1, and DNA2 to generate 3′ ssDNA overhangs.
2. RAD51 filament formation: BRCA2 loads RAD51 onto the resected ssDNA, forming a nucleoprotein filament.
3. Strand invasion: The RAD51 filament invades a homologous duplex, typically the sister chromatid, forming a D-loop.
4. DNA synthesis and resolution: DNA polymerase extends the invading strand, and the resulting recombination intermediates are resolved by structure-specific nucleases and helicases, restoring a functional replication fork.

HR is particularly important for restarting forks that have stalled at lesions that cannot be bypassed, such as interstrand crosslinks, and for repairing the DSBs that result from fork collapse.

Translesion Synthesis

Translesion synthesis (TLS) allows the replication machinery to bypass certain DNA lesions that block replicative polymerases. TLS involves the exchange of the replicative polymerase for a specialized TLS polymerase that can accommodate damaged bases in its active site:

• Y-family polymerases: Pol η, Pol ι, Pol κ, and REV1 are the major TLS polymerases in human cells. These enzymes have larger active sites that can accommodate bulky adducts, but they have low fidelity on undamaged templates.
• Bypass mechanisms: Pol η can accurately bypass CPDs by inserting two adenines opposite the lesion. Pol κ can bypass benzo[a]pyrene adducts, while REV1 inserts a cytosine opposite abasic sites.
• Two-polymerase switching: For many lesions, a two-step mechanism is used. A " inserter" polymerase (such as REV1) inserts a nucleotide opposite the lesion, and an "extender" polymerase (such as Pol ζ) extends from the mismatched terminus.

TLS is a double-edged sword: it allows replication to continue past lesions, but it is error-prone and can introduce mutations. The choice between TLS and HR is regulated by PCNA ubiquitination. Monoubiquitination of PCNA at lysine 164 promotes TLS, while polyubiquitination promotes HR.

Fork Regression and Reversal

Fork regression is a remodeling process in which the stalled fork reverses, annealing the two nascent strands and extruding the newly synthesized DNA as a fourth arm. This creates a structure resembling a Holliday junction, known as a "chicken foot." The Replication Fork Reversal page provides a detailed illustration of this structure.

Fork reversal serves several functions:

• Lesion bypass: The reversed fork allows the lesion to be bypassed using the newly synthesized sister strand as a template, a process called template switching.
• Stabilization: Fork reversal provides a stable platform for DNA repair proteins to access the lesion.
• Time to repair: Reversal gives the cell time to repair the lesion before replication resumes.

Key enzymes involved in fork regression include SMARCAL1, ZRANB3, and HLTF, which are DNA translocases that catalyze the reversal reaction. After the lesion is repaired or bypassed, the reversed fork must be restored to a normal fork structure, a process that requires the RECQ1 helicase and the annealing activity of RAD52.

Experimental Methods to Study Fork Stalling

Studying replication fork stalling requires techniques that can visualize fork dynamics at the single-molecule level or capture the molecular events occurring at stalled forks.

DNA Fiber Analysis

DNA fiber analysis is a powerful technique for measuring replication fork dynamics in cells. The method involves:

1. Labeling: Cells are sequentially incubated with two thymidine analogs, typically 5-iodo-2′-deoxyuridine (IdU) followed by 5-chloro-2′-deoxyuridine (CldU), each for a defined period (typically 20–30 minutes).
2. Spreading: Cells are lysed on a microscope slide, and the genomic DNA is stretched along the slide by gravity or capillary action.
3. Detection: The incorporated analogs are detected by immunofluorescence using antibodies that distinguish IdU and CldU.
4. Analysis: The lengths of the labeled tracks are measured by fluorescence microscopy. Fork speed is calculated by dividing the track length by the labeling time. Fork stalling is detected as a shortened second track, while fork collapse is indicated by the presence of broken or asymmetric tracks.

DNA fiber analysis can also measure origin firing, fork asymmetry, and the frequency of stalled forks. It is a relatively simple and quantitative method that provides direct evidence of fork stalling in response to various treatments.

2D Gel Electrophoresis

Two-dimensional (2D) gel electrophoresis is used to analyze replication intermediates at specific genomic loci. The technique separates DNA molecules based on both size and shape:

1. First dimension: DNA is digested with a restriction enzyme and separated by size on a low-percentage agarose gel.
2. Second dimension: The lane is excised, rotated 90°, and run on a higher-percentage gel at lower voltage. This separates molecules based on their shape, allowing replication intermediates (which are branched) to be distinguished from linear DNA.

Replication intermediates form characteristic arcs on the 2D gel. Fork stalling at a specific locus produces a "pause spot" on the arc, indicating an accumulation of replication intermediates at that position. This technique is particularly useful for studying fork stalling at defined genomic regions, such as replication fork barriers in ribosomal DNA or centromeres.

ChIP and Replication Fork ChIP

Chromatin immunoprecipitation (ChIP) can be adapted to study proteins at replication forks. In standard ChIP, proteins are crosslinked to DNA, the chromatin is sheared, and specific protein-DNA complexes are immunoprecipitated. The associated DNA is then analyzed by quantitative PCR or sequencing.

Replication fork ChIP (RF-ChIP) is a specialized variant that enriches for replication fork-associated DNA. The method involves:

1. Labeling: Cells are pulse-labeled with IdU to mark newly replicated DNA.
2. Crosslinking and immunoprecipitation: Proteins of interest are crosslinked and immunoprecipitated.
3. Detection: The associated DNA is analyzed by slot blot or qPCR using an anti-IdU antibody to detect the newly replicated DNA.

RF-ChIP allows researchers to determine whether a specific protein (e.g., ATR, RAD51, or SMARCAL1) is present at stalled forks. It can be combined with high-throughput sequencing (ChIP-seq) to map protein binding at stalled forks genome-wide.

Consequences of Unresolved Fork Stalling

When fork stalling cannot be resolved, the consequences are severe and can have long-lasting effects on genome integrity.

Double-Strand Break Formation

The most immediate consequence of unresolved fork stalling is fork collapse, which generates a one-ended DSB. This occurs through several mechanisms:

• Nucleolytic cleavage: Structure-specific nucleases, such as MUS81-EME1 and SLX4, can cleave the stalled fork structure, generating a DSB.
• Replication run-off: If the helicase continues to unwind ahead of the stalled polymerase, the resulting ssDNA can be cleaved by nucleases, or the fork can collapse when the unwound region becomes too long.
• Fork reversal and cleavage: Regressed forks can be cleaved by nucleases such as GEN1, converting the reversed fork into a DSB.

One-ended DSBs are particularly dangerous because they cannot be repaired by canonical non-homologous end joining, which requires two DNA ends. Instead, they must be repaired by homologous recombination, which requires a homologous template (the sister chromatid). If HR is defective, as in BRCA1 or BRCA2 mutant cells, these DSBs are repaired by error-prone pathways, leading to chromosomal rearrangements.

Genomic Instability and Disease

Persistent fork stalling and the resulting genomic instability are hallmarks of cancer. The link between replication stress and cancer is well-established:

• Oncogene-induced replication stress: Activation of oncogenes such as MYC, RAS, and cyclin E causes deregulated origin firing and increased fork stalling, creating a state of chronic replication stress that drives tumorigenesis.
• Cancer predisposition syndromes: Mutations in genes involved in fork protection and restart, including BRCA1, BRCA2, BLM, WRN, and FANCM, predispose individuals to cancer. These genes are essential for maintaining fork stability under conditions of replication stress.
• Genomic instability: Unresolved fork stalling leads to chromosomal breaks, translocations, and copy number alterations, which are characteristic features of cancer genomes.

In addition to cancer, replication fork stalling has been linked to premature aging. Mutations in the WRN and BLM helicases cause Werner and Bloom syndromes, respectively, which are characterized by genomic instability and accelerated aging. The accumulation of unrepaired replication stress over time contributes to cellular senescence and organismal aging.

Common Pitfalls and Study Tips

Misconceptions

Students frequently encounter several misconceptions when studying replication fork stalling:

1. "Stalling is always bad": Fork stalling is a normal and frequent event. Cells have evolved sophisticated mechanisms to manage it. Problems arise only when stalling is excessive or when the resolution mechanisms are defective.

1. "The helicase and polymerase always stop together": In reality, helicase-polymerase uncoupling is a key feature of fork stalling. The helicase often continues unwinding after the polymerase halts, generating ssDNA that activates the checkpoint.

1. "ATR and ATM are the same": ATR is the primary kinase activated by replication fork stalling, responding to RPA-coated ssDNA. ATM responds primarily to DSBs. While there is crosstalk, they are distinct pathways with different upstream sensors and downstream effectors.

1. "TLS is always mutagenic": While TLS polymerases are error-prone on undamaged templates, some TLS events are accurate. For example, Pol η correctly inserts two adenines opposite a CPD, preventing mutations.

1. "Fork reversal is always protective": While fork reversal can stabilize stalled forks and promote repair, excessive or uncontrolled fork reversal can lead to fork collapse and genomic instability. The regulation of fork reversal is critical.

Key Takeaways

• Replication fork stalling is a frequent event caused by DNA lesions, secondary structures, protein barriers, and nucleotide depletion.
• The key molecular event in fork stalling is helicase-polymerase uncoupling, which generates RPA-coated ssDNA.
• ATR/CHK1 signaling is the central checkpoint pathway activated by fork stalling, coordinating cell cycle arrest, origin suppression, and fork stabilization.
• Cells restart stalled forks through homologous recombination, translesion synthesis, or fork regression and template switching.
• Unresolved fork stalling leads to DSB formation and genomic instability, contributing to cancer and aging.
• DNA fiber analysis, 2D gel electrophoresis, and RF-ChIP are key experimental approaches for studying fork stalling.

Frequently Asked Questions

What is replication fork stalling?

Replication fork stalling is the slowing or complete halting of the replication machinery when it encounters an obstacle on the DNA template. This can be caused by DNA lesions, secondary structures, protein-DNA barriers, or nucleotide depletion. Stalling is a frequent event that activates the DNA damage response and must be resolved to complete genome duplication.

What causes replication fork stalling?

Common causes include DNA lesions (bulky adducts, pyrimidine dimers, abasic sites, crosslinks), DNA secondary structures (hairpins, G-quadruplexes, R-loops), protein-DNA barriers (transcription complexes, trapped topoisomerases), and nucleotide depletion. Endogenous sources arise from normal metabolism, while exogenous sources include UV radiation, chemical mutagens, and chemotherapeutic drugs.

How does replication fork stalling lead to DNA damage?

Fork stalling generates ssDNA through helicase-polymerase uncoupling. This ssDNA is vulnerable to nucleolytic attack and can form secondary structures. If the stall persists, the fork can collapse, generating a one-ended DSB. Additionally, stalled forks can be cleaved by structure-specific nucleases, and regressed forks can be processed into DSBs. These DSBs are potent inducers of genomic instability.

What is the role of ATR in replication fork stalling?

ATR is the master regulator of the replication checkpoint. It is recruited to stalled forks through its interaction with ATRIP, which binds RPA-coated ssDNA. ATR is activated by TopBP1 and phosphorylates CHK1, which in turn orchestrates cell cycle arrest, suppression of origin firing, and stimulation of dNTP synthesis. ATR also directly phosphorylates fork remodeling factors to stabilize stalled forks and prevent their collapse.

How do cells restart a stalled replication fork?

Cells use several mechanisms to restart stalled forks. Homologous recombination can restart collapsed forks through strand invasion and DNA synthesis. Translesion synthesis allows polymerases to bypass lesions directly. Fork regression creates a reversed fork that permits template switching and lesion bypass. The choice of mechanism depends on the nature of the obstacle and the extent of fork damage.

What is the difference between replication fork stalling and replication fork collapse?

Fork stalling is a reversible pause in fork progression that can be resolved by restart mechanisms. The fork remains structurally intact, and DNA synthesis can resume. Fork collapse is an irreversible event in which the fork structure is destroyed, typically by nuclease cleavage, generating a one-ended DSB. Collapsed forks require homologous recombination for restart.

How is replication fork stalling studied experimentally?

Key techniques include DNA fiber analysis, which measures fork speed and stalling at the single-molecule level; 2D gel electrophoresis, which visualizes replication intermediates at specific loci; and replication fork ChIP, which identifies proteins bound at stalled forks. Additional methods include electron microscopy for visualizing fork structures and genetic assays for measuring recombination or mutagenesis.

Key Takeaways

• Replication fork stalling is a frequent, normal event caused by diverse obstacles, including DNA lesions, secondary structures, protein barriers, and nucleotide depletion.
• Helicase-polymerase uncoupling generates RPA-coated ssDNA, which is the critical signal that activates the ATR/CHK1 replication checkpoint.
• The ATR/CHK1 pathway coordinates cell cycle arrest, suppression of new origin firing, and physical stabilization of stalled forks to prevent collapse.
• Stalled forks are restarted through homologous recombination, translesion synthesis, or fork regression with template switching, depending on the obstacle and damage context.
• Unresolved fork stalling leads to DSB formation, chromosomal rearrangements, and genomic instability, which are central drivers of cancer and aging.
• DNA fiber analysis, 2D gel electrophoresis, and replication fork ChIP are essential experimental tools for dissecting fork stalling mechanisms.
• Understanding fork stalling is fundamental to comprehending genome maintenance, cancer biology, and the mechanisms of action of many chemotherapeutic drugs.

Further Reading

• Qiu S et al. Replication Fork Reversal and Protection. Frontiers in cell and developmental biology. 2021. PubMed 34041245
• Mirkin EV, Mirkin SM. Replication fork stalling at natural impediments. Microbiology and molecular biology reviews : MMBR. 2007. PubMed 17347517
• Sethi A et al. How DNA secondary structures drive replication fork instability. DNA repair. 2025. PubMed 41370868
• Scully R et al. Recombination and restart at blocked replication forks. Current opinion in genetics & development. 2021. PubMed 34464818
• Westhorpe R, Roske JJ, Yeeles JTP. Mechanisms controlling replication fork stalling and collapse at topoisomerase 1 cleavage complexes. Molecular cell. 2024. PubMed 39236719
• Ma J et al. CK2-dependent degradation of CBX3 dictates replication fork stalling and PARP inhibitor sensitivity. Science advances. 2024. PubMed 38781342

Related Clinical & Scientific Guides

• MAPK Pathway: Mechanism, Function, and Clinical Relevance
• Mammalian Cell Culture Bioreactors: A Practical Guide
• Nucleotide Formation: Biosynthesis and Assembly of DNA/RNA Building Blocks