# Non-Homologous End Joining Repair: Mechanism and Significance

## Introduction to Non-Homologous End Joining Repair

Non-homologous end joining (NHEJ) is one of the two principal pathways for repairing DNA double-strand breaks (DSBs) in eukaryotic cells. Unlike [homologous recombination](/knowledge/molecular-biology/homologous-recombination), which requires a sister chromatid as a template for accurate repair, NHEJ directly ligates the two broken DNA ends together with minimal or no sequence homology. This direct ligation makes NHEJ available throughout the cell cycle, but it is particularly critical during the G1 phase, when sister chromatids are not yet available for [homologous recombination](/knowledge/molecular-biology/homologous-recombination).

### What is NHEJ?

NHEJ is a DNA repair pathway that detects broken DNA ends, protects them from further degradation, processes them to create compatible termini, and finally ligates them back together. The pathway is described as "non-homologous" because it does not require a homologous template to guide repair. Instead, the repair machinery aligns the two broken ends based on short stretches of microhomology (typically 1–4 base pairs) that may be exposed during end processing, or simply ligates them directly if the ends are compatible.

The pathway is evolutionarily conserved from bacteria to humans. In bacteria, a simplified version involving Ku and ligase D exists, while eukaryotes have elaborated the system with additional factors that increase efficiency and regulatory control. In human cells, NHEJ repairs the majority of ionizing radiation-induced DSBs and is essential for V(D)J recombination, the process that generates antibody and T-cell receptor diversity in the immune system.

### NHEJ vs. Homologous Recombination

The two major DSB repair pathways differ fundamentally in their requirements and outcomes:

| Feature | NHEJ | Homologous Recombination |
|---|---|---|
| Template requirement | None | Sister chromatid (homologous sequence) |
| Cell cycle phase | All phases, especially G1 | S and G2 phases |
| Repair accuracy | Error-prone (small indels common) | High-fidelity (template-directed) |
| End processing | Limited, often minimal | Extensive 5′ end resection required |
| Key proteins | Ku70/Ku80, DNA-PKcs, Ligase IV | MRN complex, CtIP, RAD51, BRCA2 |
| Primary function | Quick repair, immune diversity | Accurate repair, replication restart |

The choice between these pathways is governed by cell cycle stage and the extent of end resection. When a DSB occurs, the MRN complex (MRE11-RAD50-NBS1) initially binds and can initiate resection. If resection proceeds beyond approximately 20–30 nucleotides, the single-stranded DNA overhangs commit the cell to homologous recombination. In G1, resection is actively suppressed by 53BP1 and its effectors, favoring NHEJ. For a deeper comparison of these pathways, see [Homologous Recombination](/knowledge/molecular-biology/homologous-recombination).

## The Double-Strand Break Problem

A double-strand break is among the most cytotoxic forms of DNA damage. A single unrepaired DSB is sufficient to trigger cell cycle arrest and, if persistent, apoptosis. Unlike base lesions or single-strand breaks, which can be repaired using the intact complementary strand as a template, a DSB physically disrupts the continuity of both DNA strands. This means there is no intact template for accurate repair, and the chromosome is at risk of being lost entirely during mitosis.

### Sources of DSBs

DSBs arise from both exogenous and endogenous sources:

- **Ionizing radiation**: X-rays, gamma rays, and particle radiation deposit energy that can directly break the DNA backbone. A typical dose of 1 Gy of gamma radiation induces approximately 20–40 DSBs per cell.
- **Reactive oxygen species (ROS)**: Endogenous metabolism generates superoxide, hydrogen peroxide, and hydroxyl radicals. Hydroxyl radicals can abstract hydrogen atoms from deoxyribose, leading to sugar fragmentation and strand breaks. When two breaks occur in close proximity on opposite strands, a DSB results.
- **[Replication fork collapse](/knowledge/molecular-biology/replication-fork-collapse)**: When the replication machinery encounters a nick or a bulky lesion on the template strand, the fork can stall and collapse, generating a one-ended DSB. These are normally repaired by homologous recombination, but can be aberrantly processed by NHEJ if they occur in G1.
- **Topoisomerase poisons**: Chemotherapeutic agents such as etoposide trap topoisomerase II in a covalent complex with DNA, preventing religation and generating DSBs.
- **Programmed DSBs**: During V(D)J recombination and class switch recombination in lymphocytes, the RAG endonuclease and activation-induced cytidine deaminase (AID) deliberately introduce DSBs as part of the immune diversification program.

### Consequences of Unrepaired DSBs

If a DSB is not repaired, the consequences are severe. During mitosis, the broken chromosome lacks a functional centromere-kinetochore attachment on one side, leading to anaphase bridge formation and chromosome breakage. The cell may undergo apoptosis or senescence. If the cell survives, the broken ends can be illegitimately joined to other chromosomes, producing:

- **Chromosomal translocations**: Fusion of non-homologous chromosomes, such as the BCR-ABL fusion in chronic myeloid leukemia.
- **Deletions**: Loss of genetic material between two breaks on the same chromosome.
- **Inversions**: Reversal of a chromosomal segment when ends are joined in the wrong orientation.

These rearrangements are hallmarks of cancer genomes. The critical importance of DSB repair is underscored by the fact that mutations in DSB repair genes cause severe human syndromes, including ataxia-telangiectasia, Nijmegen breakage syndrome, and various immunodeficiencies.

## Key Proteins in NHEJ

The core NHEJ machinery in human cells consists of seven principal factors. Each plays a distinct role in recognizing, protecting, processing, and ligating broken DNA ends. For a comprehensive overview of these factors, see [Non Homologous End Joining Proteins](/knowledge/molecular-biology/non-homologous-end-joining-proteins).

### Ku70/Ku80 Heterodimer

The Ku heterodimer, composed of Ku70 (XRCC6, 70 kDa) and Ku80 (XRCC5, 86 kDa), is the first protein to bind DSB ends. Ku has an unusual ring-like structure that threads onto the [DNA double helix](/blog/guides/dna-double-helix), making sequence-independent contacts with the sugar-phosphate backbone. This binding is extremely tight (dissociation constant in the picomolar range) and protects the DNA ends from exonucleolytic degradation.

Ku is abundant in the nucleus—approximately 400,000 molecules per cell—ensuring rapid loading at break sites. Once bound, Ku serves as a platform for recruiting the other NHEJ factors. It also has ATPase and helicase activities, though their physiological significance in NHEJ remains debated.

### DNA-PKcs and Artemis

DNA-dependent [protein kinase](/knowledge/molecular-biology/protein-kinase) catalytic subunit (DNA-PKcs) is a 469 kDa serine/threonine kinase that belongs to the phosphatidylinositol 3-kinase-like kinase (PIKK) family. It is recruited to DNA ends by Ku, and together they form the DNA-PK holoenzyme. DNA-PKcs undergoes autophosphorylation at multiple sites, including the ABCDE cluster (Ser2612, Ser2624, Ser2638, Thr2639, Ser2640) and the PQR cluster (Ser2023, Ser2029, Ser2041, Ser2052, Ser2056). These phosphorylation events induce conformational changes that are required for end processing and for releasing the kinase from the DNA end to allow ligation.

Artemis is a nuclease that forms a stable complex with DNA-PKcs. Artemis alone has weak 5′→3′ exonuclease activity, but when phosphorylated by DNA-PKcs, it acquires endonuclease activity that can open hairpin structures and trim overhanging ends. This activity is essential for V(D)J recombination, where RAG-generated hairpin intermediates must be opened, and for repairing a subset of radiation-induced DSBs with damaged or blocked termini.

### Ligation Complex: XRCC4, Ligase IV, XLF

DNA ligase IV is the dedicated ligase for NHEJ. Unlike ligase I (replication) or ligase III ([base excision repair](/knowledge/molecular-biology/base-excision-repair)), ligase IV has a unique ability to ligate non-complementary ends, albeit with low efficiency. It forms a tight complex with XRCC4 (X-ray repair cross-complementing protein 4), a scaffolding protein that stabilizes ligase IV and stimulates its activity. The XRCC4-Ligase IV complex has a dissociation constant of approximately 10 nM, and the interaction is essential for ligase IV stability—in the absence of XRCC4, ligase IV is degraded.

XLF (XRCC4-like factor, also called Cernunnos) is a paralog of XRCC4 that forms filaments along DNA and stimulates ligase IV activity by promoting the alignment of the two DNA ends. XLF can also interact with Ku and DNA-PKcs, bridging the gap between the end-binding complex and the ligation machinery.

PAXX (paralog of XRCC4 and XLF) is a more recently identified factor that also stimulates NHEJ, though its precise role is less well understood. It appears to function redundantly with XLF in some contexts.

## Step-by-Step Mechanism of NHEJ

The NHEJ pathway proceeds through a series of ordered steps that can be divided into three phases: recognition and synapsis, end processing, and ligation. The entire process typically completes within 30 minutes to a few hours in cultured cells. For a visual overview of the pathway, see [Non Homologous End Joining Pathway](/knowledge/molecular-biology/non-homologous-end-joining-pathway).

### Recognition and Synapsis

1. **Ku loading**: The Ku70/Ku80 heterodimer binds to each broken DNA end within seconds of break formation. Ku binding requires a free DNA end with a 5′ phosphate and a 3′ hydroxyl group, though it can accommodate a variety of end structures including blunt ends, 5′ overhangs, and 3′ overhangs.

2. **DNA-PKcs recruitment**: Ku recruits DNA-PKcs to the DNA end, forming the DNA-PK holoenzyme. This binding requires ATP and is accompanied by a conformational change in DNA-PKcs that activates its kinase activity.

3. **Synapsis**: The two DNA-PK complexes at opposite ends of the break interact with each other, bringing the two DNA ends into close proximity. This synaptic complex stabilizes the broken ends and prevents them from diffusing apart. The synaptic complex can span gaps of at least 20 base pairs of missing DNA.

4. **Autophosphorylation**: DNA-PKcs undergoes autophosphorylation at the ABCDE and PQR clusters. This is a critical regulatory step—phosphorylation at ABCDE promotes end processing, while phosphorylation at PQR is required for the release of DNA-PKcs from the DNA end, allowing access to the ligation machinery.

### End Processing

The ends of a DSB are rarely directly ligatable. Ionizing radiation produces ends with damaged nucleotides, abasic sites, and 3′ phosphate or 5′ hydroxyl groups that cannot be ligated. The processing phase modifies these ends to create compatible termini:

1. **Nucleotide removal**: The Artemis nuclease, activated by DNA-PKcs phosphorylation, trims 5′ and 3′ overhangs. Artemis can also open hairpin structures that form when the two strands of a DSB are covalently cross-linked.

2. **Polymerase activity**: Several DNA polymerases participate in NHEJ end processing. [DNA polymerase](/blog/guides/dna-polymerase) μ and [DNA polymerase](/blog/guides/dna-polymerase) λ are members of the X-family of polymerases that can add nucleotides to DNA ends in a template-independent or template-dependent manner. Polymerase μ is particularly notable for its ability to add nucleotides across a gap without a template, which contributes to the insertion of random nucleotides at repair junctions.

3. **End alignment**: The two ends are aligned using short regions of microhomology (1–4 base pairs) that become exposed after resection. The alignment is stabilized by XLF, which forms filaments that bridge the two DNA molecules.

4. **Cleavage of damaged ends**: The aprataxin and PNKP-like factor (APLF) and polynucleotide kinase 3′-phosphatase (PNKP) remove 3′ phosphates and phosphorylate 5′ hydroxyl groups, respectively, converting damaged ends into substrates for ligase IV.

### Ligation and Release

1. **Ligase IV recruitment**: The XRCC4-Ligase IV complex is recruited to the synaptic complex through interactions with Ku and XLF. Ligase IV catalyzes the ATP-dependent formation of a phosphodiester bond between the 3′ hydroxyl of one strand and the 5′ phosphate of the other.

2. **Ligation of both strands**: Ligase IV ligates one strand, then the other. The two ligation events can occur sequentially, with a transient nicked intermediate.

3. **Complex disassembly**: After ligation, the NHEJ factors must be removed from the repaired DNA. DNA-PKcs autophosphorylation promotes its dissociation, and the ubiquitin ligase RNF8/RNF168 pathway targets Ku for degradation. The proteasome-mediated degradation of Ku is essential for clearing the repair complex and allowing transcription and replication to resume.

## Why NHEJ Is Error-Prone

NHEJ is frequently described as error-prone because it often introduces small insertions or deletions (indels) at the repair junction. This is a direct consequence of the end processing steps that are required to make incompatible ends ligatable.

### Mechanisms of Indels

The two main sources of sequence alterations at NHEJ junctions are:

- **Deletions**: When Artemis or other nucleases trim overhanging ends, nucleotides are lost. The extent of deletion depends on the structure of the original break and the degree of processing required. Deletions of 1–20 base pairs are common, though larger deletions can occur if the ends are extensively resected before NHEJ commits.

- **Insertions**: DNA polymerases μ and λ can add nucleotides at the junction. Polymerase μ can add nucleotides in a template-independent manner, incorporating random bases. This is particularly prominent during V(D)J recombination, where terminal deoxynucleotidyl transferase (TdT), a related polymerase, adds N-nucleotides at the junctions.

The net result is that NHEJ junctions typically contain a few base pairs of sequence that differ from the original undamaged DNA. However, it is important to note that NHEJ can be accurate. If the two ends are compatible (e.g., blunt ends with 5′ phosphates and 3′ hydroxyls), ligase IV can join them without any nucleotide loss or addition. In this case, the repair is error-free. The error-prone nature of NHEJ is therefore a consequence of the flexibility required to handle diverse break structures, not an inherent property of the ligation reaction itself.

### Role in V(D)J Recombination

The error-prone nature of NHEJ is exploited during V(D)J recombination to generate antibody diversity. In this process, the RAG1/RAG2 endonuclease introduces DSBs at recombination signal sequences flanking V, D, and J gene segments. The breaks are processed by the NHEJ machinery, with Artemis opening the hairpin intermediates and TdT adding random nucleotides at the junctions.

The junctional diversity generated by NHEJ is the primary source of antibody and T-cell receptor diversity. The CDR3 region of immunoglobulins, which is the major antigen-contacting loop, is precisely the region where NHEJ-mediated insertions and deletions are concentrated. This allows a limited number of gene segments to generate an enormous repertoire of antigen receptors—estimated at 10¹¹ possible combinations in humans.

## Methods to Study NHEJ

Several experimental approaches have been developed to study NHEJ, ranging from simple cell-based assays to biochemical reconstitution of the entire pathway.

### Reporter Assays

The most widely used NHEJ reporter assays are based on the restoration of a fluorescent protein or selectable marker after repair of an induced DSB. A typical design uses a GFP gene that has been inactivated by the insertion of an I-SceI endonuclease recognition site. When I-SceI is expressed, it creates a DSB at the site. If NHEJ repairs the break, the reading frame may be restored, producing a functional GFP that can be detected by flow cytometry.

The advantage of this system is that it measures NHEJ in living cells under physiological conditions. Variants of the assay can distinguish between NHEJ and homologous recombination by using different reporter constructs. For example, a homologous recombination reporter uses two tandem copies of a mutated GFP gene, where repair by homologous recombination restores one functional copy.

### Biochemical Reconstitution

The NHEJ pathway can be reconstituted in vitro using purified proteins and defined DNA substrates. A typical reaction contains:

- 50 nM Ku70/Ku80
- 50 nM DNA-PKcs
- 25 nM XRCC4-Ligase IV complex
- 25 nM XLF
- 1 mM ATP
- 10 mM Tris-HCl (pH 7.5)
- 50 mM KCl
- 5 mM MgCl₂
- 1 mM DTT

Reactions are incubated at 37°C for 30–60 minutes, and the products are analyzed by denaturing polyacrylamide gel electrophoresis. This approach allows precise control over the reaction conditions and has been instrumental in defining the minimal requirements for NHEJ. It was through such reconstitution experiments that the essential role of XLF in stimulating ligation was discovered.

### Cell-Based Approaches

Chromatin immunoprecipitation (ChIP) is used to measure the recruitment of NHEJ factors to DSBs in living cells. In a typical experiment, cells are irradiated or treated with a radiomimetic drug, then cross-linked with formaldehyde. The chromatin is sheared, and antibodies against specific NHEJ proteins are used to immunoprecipitate DNA fragments bound to those proteins. Quantitative PCR with primers flanking the break site reveals the kinetics of protein recruitment.

CRISPR-based knockout screens have been used to identify genes required for NHEJ. In these screens, a library of guide RNAs targeting thousands of genes is introduced into cells, and the cells are then challenged with a DSB-inducing agent. Cells that survive must have functional NHEJ. Sequencing the guide RNAs in surviving cells identifies genes whose knockout sensitizes cells to DSBs. For more on how CRISPR interfaces with NHEJ, see [Non Homologous End Joining CRISPR](/knowledge/molecular-biology/non-homologous-end-joining-crispr).

## NHEJ in Human Disease and Therapy

Given the central role of NHEJ in maintaining genome stability and generating immune diversity, it is not surprising that defects in this pathway cause severe human diseases.

### Diseases Linked to NHEJ Defects

Mutations in NHEJ genes cause a spectrum of disorders characterized by immunodeficiency, radiosensitivity, and developmental abnormalities:

- **Ligase IV syndrome**: Mutations in LIG4 cause microcephaly, growth retardation, pancytopenia, and severe combined immunodeficiency. Cells from these patients show markedly reduced DSB repair and hypersensitivity to ionizing radiation.

- **Cernunnos/XLF deficiency**: Mutations in XLF cause a form of severe combined immunodeficiency with microcephaly and growth retardation. The phenotype is similar to but generally milder than Ligase IV syndrome.

- **Artemis deficiency**: Mutations in DCLRE1C (encoding Artemis) cause radiosensitive severe combined immunodeficiency (RS-SCID). These patients lack T and B cells because V(D)J recombination is blocked at the hairpin-opening step.

- **DNA-PKcs deficiency**: Mutations in PRKDC cause a rare form of RS-SCID with additional neurological features.

- **Nijmegen breakage syndrome**: Caused by mutations in NBN (encoding nibrin, a component of the MRN complex), this disorder is characterized by microcephaly, immunodeficiency, and a strong predisposition to lymphoid malignancies.

### NHEJ in CRISPR Gene Editing

The CRISPR-Cas9 system introduces a DSB at a specific genomic locus guided by a single-guide RNA. Once the break is made, the cell must repair it. In most cell types, NHEJ is the dominant repair pathway, and the resulting indels frequently disrupt the coding sequence of the targeted gene.

This property is exploited for gene knockout experiments. By designing a guide RNA that targets the coding region of a gene, researchers can introduce frameshift mutations that lead to premature stop codons and nonsense-mediated decay of the mRNA. The efficiency of this approach depends on the relative activities of NHEJ and homologous recombination in the cell type being used. In cells where homologous recombination is active, such as embryonic stem cells, a homologous recombination donor template can be provided to achieve precise gene editing instead of error-prone NHEJ.

The error-prone nature of NHEJ is also a limitation for therapeutic gene editing, where precise correction of a mutation is desired. Strategies to suppress NHEJ and favor homologous recombination include using small-molecule inhibitors of DNA-PKcs (such as NU7441 or M3814) or engineering Cas9 variants that produce longer overhangs that are less favorable substrates for NHEJ.

## Common Pitfalls and Exam Tips

Students frequently struggle with several aspects of NHEJ. Understanding these common misconceptions will help you avoid them in exams and in the laboratory.

### Misconceptions

1. **"NHEJ is always error-prone"**: This is incorrect. NHEJ can be perfectly accurate when the DNA ends are compatible and require no processing. The error-prone nature of NHEJ is a consequence of end processing, not an intrinsic property of the ligation reaction.

2. **"NHEJ and homologous recombination are redundant"**: They are not redundant. They operate at different cell cycle stages, use different proteins, and have different outcomes. NHEJ is fast and available throughout the cell cycle; homologous recombination is slow, requires a sister chromatid, and is restricted to S/G2.

3. **"Ku binds to single-stranded DNA"**: Ku binds specifically to double-stranded DNA ends. It does not bind single-stranded DNA with high affinity. This is an important distinction because single-stranded DNA is the substrate for homologous recombination.

4. **"DNA-PKcs is the ligase"**: DNA-PKcs is a kinase, not a ligase. The ligation step is performed by DNA ligase IV in complex with XRCC4. DNA-PKcs regulates the pathway through phosphorylation but does not catalyze phosphodiester bond formation.

5. **"NHEJ only repairs radiation-induced breaks"**: NHEJ repairs all types of DSBs, including those generated by replication stress, topoisomerase poisons, and programmed breaks during V(D)J recombination.

### Memory Aids

- **Ku = "Kuhn" (German for "cow")**: The Ku protein was named after a patient with autoimmune disease whose antibodies recognized it. The name has no functional meaning, but you can remember it as the "first responder" that binds DNA ends.

- **The order of events**: **K**u binds, **D**NA-PKcs is recruited, **A**rtemis processes, **L**igase IV ligates. Remember "KDAL" or "Ku Does All Ligation" (even though Ku doesn't ligate—the mnemonic just helps with the order).

- **DNA-PKcs phosphorylation**: The ABCDE cluster promotes end processing; the PQR cluster promotes release. "A for Access, P for Parting."

- **XRCC4 and XLF**: Both are scaffolding proteins. XRCC4 is the "workhorse" that stabilizes ligase IV; XLF is the "helper" that stimulates ligation. XLF is also called Cernunnos, named after the Celtic horned god—remember "XLF has horns" (it forms filaments that look like horns on DNA).

## Frequently Asked Questions

### What is non-homologous end joining repair?

Non-homologous end joining repair is a DNA double-strand break repair pathway that directly ligates broken DNA ends together without requiring a homologous template. It is the dominant DSB repair pathway in mammalian cells, particularly in the G1 phase of the cell cycle, and is essential for V(D)J recombination in the immune system.

### How does non-homologous end joining repair work?

NHEJ works through a series of ordered steps: (1) the Ku70/Ku80 heterodimer binds to the broken DNA ends, (2) DNA-PKcs is recruited and forms a synaptic complex that brings the ends together, (3) end processing factors such as Artemis and DNA polymerases modify the ends to make them ligatable, and (4) DNA ligase IV in complex with XRCC4 and XLF seals the break.

### What is an example of non-homologous end joining?

The most prominent example is V(D)J recombination, where NHEJ joins V, D, and J gene segments to generate antibody diversity. Another example is the repair of ionizing radiation-induced DSBs. In the laboratory, CRISPR-Cas9-induced breaks are predominantly repaired by NHEJ, which is why CRISPR is commonly used to generate gene knockouts.

### Why is NHEJ considered error-prone?

NHEJ is considered error-prone because the end processing steps often remove nucleotides (deletions) or add nucleotides (insertions) at the repair junction. These indels can alter the reading frame of genes. However, NHEJ can be accurate when the ends are compatible and require no processing.

### What proteins are involved in NHEJ?

The core NHEJ proteins are Ku70/Ku80, DNA-PKcs, Artemis, XRCC4, DNA ligase IV, XLF, and PAXX. Additional factors include DNA polymerases μ and λ, PNKP, APLF, and the MRN complex, which participates in the initial recognition of breaks.

### When does NHEJ occur in the cell cycle?

NHEJ occurs in all phases of the cell cycle but is particularly important in G1, when sister chromatids are not available for homologous recombination. In S and G2 phases, both NHEJ and homologous recombination are active, and the choice between them is regulated by the extent of end resection.

### How is NHEJ used in CRISPR?

CRISPR-Cas9 introduces a DSB at a targeted genomic locus. In most cell types, NHEJ repairs this break, often introducing small indels that disrupt the target gene. This is the basis for CRISPR-mediated gene knockout. For precise gene editing, a homologous recombination donor template must be provided, and NHEJ must be suppressed.

## Key Takeaways

- NHEJ is the primary DSB repair pathway in mammalian cells and functions throughout the cell cycle, especially in G1.
- The pathway is defined by direct ligation of broken ends without a homologous template, making it faster but generally more error-prone than homologous recombination.
- The core machinery consists of Ku70/Ku80, DNA-PKcs, Artemis, XRCC4, DNA ligase IV, and XLF, each with a distinct role in recognition, processing, and ligation.
- NHEJ is error-prone because end processing generates small insertions and deletions, but it can be accurate when ends are compatible.
- NHEJ is essential for V(D)J recombination and antibody diversity, and defects in NHEJ genes cause immunodeficiencies and radiosensitivity syndromes.
- CRISPR-Cas9 gene editing relies on NHEJ for efficient gene knockout, while therapeutic gene correction requires suppressing NHEJ in favor of homologous recombination.
- Understanding the distinction between NHEJ and homologous recombination—in terms of cell cycle dependence, accuracy, and protein requirements—is fundamental to mastering DNA repair biology.

## Further Reading

- Jin M et al. *Lactylation of XLF promotes non-homologous end-joining repair and chemoresistance in cancer*. Molecular cell. 2025. [PubMed 40680721](https://doi.org/10.1016/j.molcel.2025.06.019)
- Zhu S, Peng A. *Non-homologous end joining repair in Xenopus egg extract*. Scientific reports. 2016. [PubMed 27324260](https://doi.org/10.1038/srep27797)
- Li Y et al. *CNOT7 facilitates radiation resistance in colorectal cancer through TRIM21/XRCC6-mediated non-homologous end joining repair*. Cell death & disease. 2025. [PubMed 41249119](https://doi.org/10.1038/s41419-025-08160-4)
- Chen M et al. *Kaempferol inhibits non-homologous end joining repair via regulating Ku80 stability in glioma cancer*. Phytomedicine : international journal of phytotherapy and phytopharmacology. 2023. [PubMed 37210962](https://doi.org/10.1016/j.phymed.2023.154876)
- Chen BR et al. *Senataxin and DNA-PKcs redundantly promote non-homologous end joining repair of DNA double strand breaks during V(D)J recombination*. Science advances. 2025. [PubMed 40540553](https://doi.org/10.1126/sciadv.ads5272)
- Lin YH et al. *KAP1 Deacetylation by SIRT1 Promotes Non-Homologous End-Joining Repair*. PloS one. 2015. [PubMed 25905708](https://doi.org/10.1371/journal.pone.0123935)

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* [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)