regulation of double-strand break repair

Definition

Target type: biologicalprocess

Any process that modulates the frequency, rate or extent of double-strand break repair. [GOC:BHF]

Double-strand break (DSB) repair is a critical cellular process that safeguards genome integrity by mending breaks in both strands of DNA. This intricate process involves multiple pathways, each with unique mechanisms and regulatory factors, ensuring accurate and efficient repair.

**1. Sensing and Signaling:**

* **Detection:** The initial step involves the recognition of DSBs by sensor proteins like the MRN complex (Mre11, Rad50, Nbs1). This complex binds to the broken DNA ends and activates downstream signaling pathways.
* **Activation of ATM Kinase:** The MRN complex recruits and activates the ATM kinase, a key player in the DNA damage response. ATM phosphorylation triggers a cascade of signaling events, including the phosphorylation of downstream substrates like p53 and Chk2.

**2. DNA End Processing:**

* **Resection:** The broken DNA ends are processed by nucleases, including the MRN complex and exonucleases like Exo1. This process generates 3' single-stranded DNA overhangs, essential for homologous recombination (HR) repair.
* **5' End Processing:** The 5' ends of the DSB are also processed, often by the CtIP protein, to remove damaged nucleotides and create a clean break.

**3. Repair Pathway Choice:**

* **Homologous Recombination (HR):** HR is the preferred pathway for repairing DSBs during S and G2 phases when a sister chromatid is available. HR utilizes the homologous sequence of the sister chromatid as a template for accurate repair, minimizing the risk of mutations.
* **Non-Homologous End Joining (NHEJ):** NHEJ is the primary pathway for DSB repair in G1 phase, when a sister chromatid is not available. NHEJ directly joins the broken DNA ends without using a template, but it can introduce small deletions or insertions, potentially leading to mutations.

**4. Homologous Recombination (HR) Repair:**

* **Rad51 Filament Formation:** The 3' single-stranded DNA overhangs are coated by the Rad51 protein, forming a nucleoprotein filament that searches for homologous sequences on the sister chromatid.
* **Strand Invasion and Exchange:** The Rad51 filament promotes strand invasion, where the broken DNA strand pairs with the homologous sequence on the sister chromatid, forming a Holliday junction.
* **Resolution and Repair:** The Holliday junction is processed and resolved by specific enzymes, leading to the exchange of genetic material between the broken strand and the sister chromatid, resulting in accurate repair.

**5. Non-Homologous End Joining (NHEJ) Repair:**

* **Ligase IV Complex:** NHEJ relies on the Ku70/Ku80 heterodimer, which binds to the broken DNA ends and recruits other factors, including DNA ligase IV and the XLF protein.
* **DNA End Joining:** The Ku70/Ku80 complex aligns the DNA ends, and ligase IV joins them together, restoring the broken DNA sequence.

**6. Regulation and Feedback:**

* **Checkpoint Control:** The DNA damage response activates cell cycle checkpoints, pausing the cell cycle to allow time for repair. These checkpoints are regulated by proteins like p53 and Chk2, which are activated by ATM phosphorylation.
* **Feedback Mechanisms:** The DNA damage response is tightly regulated by feedback mechanisms. For example, the accumulation of repair factors at the DSB site can inhibit further resection or promote the recruitment of specific repair proteins.

**7. Factors Influencing Repair Choice:**

* **Cell Cycle Phase:** The cell cycle stage is a major determinant of the repair pathway used. HR is favored during S and G2, while NHEJ is preferred during G1.
* **DNA Sequence Context:** The DNA sequence surrounding the break can influence the efficiency and accuracy of repair. Some sequences are more prone to recombination, while others favor NHEJ.
* **Chromatin Structure:** The chromatin environment around the break can affect repair accessibility. Open chromatin regions are more easily repaired than tightly packed regions.

**8. Consequences of Impaired Repair:**

* **Genome Instability:** Defects in DSB repair pathways can lead to genomic instability, increasing the risk of mutations, deletions, and translocations.
* **Cancer Development:** Impaired DNA repair can contribute to cancer development by allowing mutations to accumulate, potentially leading to uncontrolled cell growth.
* **Neurological Disorders:** DSB repair defects are implicated in neurological disorders such as ataxia telangiectasia, which is characterized by neurodegeneration, immune deficiencies, and an increased risk of cancer.

DSB repair is a highly regulated and complex process that is essential for maintaining genome stability. The interplay of multiple pathways, regulatory factors, and checkpoint mechanisms ensures accurate and efficient repair, safeguarding against the harmful consequences of DNA damage.'
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Proteins (5)

Compounds (129)