double-strand break repair via alternative nonhomologous end joining

Definition

Target type: biologicalprocess

An instance of double-strand break repair via nonhomologous end joining that is independent of factors important for V(D)J recombination (as opposed to classical nonhomologous end joining). It often results in a deletion with microhomology (i.e. 5-25bp homology) at the repair junction. Among different subclasses of nonhomologous end joining (NHEJ), alternative NHEJ appears to play a significant role in the etiology of mutations that arise during cancer development and treatment. [GOC:rph, PMID:18584027, PMID:21655080, Wikipedia:Microhomology-mediated_end_joining]

Alternative Non-Homologous End Joining (alt-NHEJ) is a DNA double-strand break (DSB) repair pathway that operates independently of homologous recombination (HR) and canonical NHEJ. It plays a significant role in the repair of DSBs, especially in the absence of a homologous template for HR. Alt-NHEJ is characterized by its reliance on microhomology-mediated end joining, where short stretches of identical DNA sequences at the break ends are utilized for ligation. This process often results in deletions, insertions, and other structural rearrangements at the repair site.

Here's a detailed breakdown of the alt-NHEJ process:

1. **DSB Recognition and Processing:** The initial steps involve recognition of the DSB by factors like the MRN complex (Mre11, Rad50, and Nbs1). The MRN complex initiates resection of the break ends, generating 3' single-stranded tails.

2. **Microhomology Identification:** The resected 3' tails then undergo extensive processing, often by nucleases such as CtIP and EXO1. During this processing, short stretches of microhomologies (typically 5-25 base pairs) are exposed.

3. **Microhomology-Mediated End Joining:** Once microhomologies are identified, the DNA ends are aligned, and the microhomologies are paired. This alignment brings the broken DNA strands together.

4. **Polymerization and Ligation:** DNA polymerase fills in any gaps between the microhomology regions, synthesizing new DNA. Finally, DNA ligase seals the remaining nicks, completing the repair process.

5. **Error Prone Repair:** The reliance on microhomology-mediated joining and the often imprecise nature of the process make alt-NHEJ a highly error-prone repair pathway. This can lead to deletions, insertions, and other structural rearrangements at the repair site. These rearrangements can have significant consequences for gene function and genome stability.

Key factors involved in alt-NHEJ:

* **MRN complex:** Recognizes DSBs and initiates resection.
* **CtIP and EXO1:** Nucleases involved in 3' end processing and microhomology exposure.
* **PARP1:** Poly(ADP-ribose) polymerase 1, involved in DSB recognition and signaling.
* **Ligase III and XRCC1:** Ligases involved in DNA end joining.
* **Pol θ:** A DNA polymerase that plays a central role in filling in gaps during alt-NHEJ.

Significance of alt-NHEJ:

* **Backup repair pathway:** Operates in the absence of HR, providing a mechanism for DSB repair in cells that are deficient in HR.
* **Cellular response to stress:** Plays a role in the repair of DSBs induced by DNA damaging agents, such as ionizing radiation and chemotherapy drugs.
* **Genome instability:** The error-prone nature of alt-NHEJ can lead to genetic mutations, contributing to genome instability and disease development.

Overall, alt-NHEJ is a crucial DNA repair pathway that provides an alternative route for DSB repair when HR is unavailable. While it effectively protects against DNA damage, its error-prone nature highlights the delicate balance between DNA repair and genome stability.'
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Proteins (2)

Compounds (236)