positive regulation of double-strand break repair

Definition

Target type: biologicalprocess

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

Positive regulation of double-strand break repair is a complex biological process that involves a series of coordinated steps to ensure accurate and efficient repair of DNA double-strand breaks (DSBs), which are highly deleterious lesions that can lead to genome instability, cell death, and cancer. This process is crucial for maintaining the integrity of the genome and is tightly regulated by a variety of factors.

The initial step in double-strand break repair is the recognition of the broken DNA ends. This is accomplished by specialized proteins that bind to the DSB site, such as the MRN complex (MRE11, RAD50, and NBS1), which acts as a sensor and recruits other repair proteins to the site.

Once the break is recognized, the cell must choose one of two major repair pathways: non-homologous end joining (NHEJ) or homologous recombination (HR). NHEJ is a relatively error-prone pathway that rejoins broken DNA ends directly, while HR is a more accurate pathway that uses a homologous template, such as a sister chromatid, to guide the repair process.

The choice of repair pathway is influenced by several factors, including the cell cycle stage, the nature of the break, and the availability of homologous templates. For example, NHEJ is the dominant repair pathway during G1 phase, when sister chromatids are not yet duplicated, while HR is more active during S and G2 phases, when sister chromatids are available as templates.

**Positive Regulation of NHEJ:**

- **Ku70/Ku80 heterodimer:** This protein complex binds to broken DNA ends with high affinity and acts as a scaffold for the recruitment of other NHEJ factors, such as DNA-PKcs and Ligase IV.
- **DNA-PKcs:** This protein kinase is activated by the binding of the Ku70/Ku80 complex to DNA and phosphorylates various substrates involved in NHEJ, including itself, Ku70/Ku80, and the Artemis nuclease. These phosphorylation events promote the processing of DNA ends, the assembly of the NHEJ machinery, and the ligation of the broken DNA ends.
- **XLF and XRCC4:** These proteins interact with Ligase IV and facilitate the ligation of DNA ends.
- **Artemis:** This nuclease removes short overhangs or mismatches from the DNA ends, creating a more precise substrate for ligation.

**Positive Regulation of HR:**

- **BRCA2:** This protein is a key regulator of HR and functions as a mediator between the MRN complex and RAD51, a protein that promotes the invasion of the homologous template. BRCA2 also participates in the recruitment of other HR factors, such as PALB2 and RAD51C.
- **RAD51:** This protein assembles into nucleoprotein filaments on single-stranded DNA (ssDNA) and promotes the invasion of the homologous template.
- **ATM:** This protein kinase is activated by DSBs and phosphorylates a variety of substrates involved in DNA repair, including BRCA1, BRCA2, and RAD51, leading to the activation of the HR pathway.
- **CtIP:** This protein is involved in the 5' to 3' resection of DSB ends, creating ssDNA that can be bound by RAD51.
- **RAD54:** This protein facilitates the pairing and strand exchange between the broken DNA and the homologous template.

**Other Positive Regulators:**

- **p53:** This tumor suppressor protein can activate the expression of various DNA repair genes, including those involved in both NHEJ and HR.
- **Histone modifications:** Changes in histone acetylation and methylation can influence the accessibility of DNA to repair proteins and thus regulate DNA repair.
- **MicroRNAs:** These small non-coding RNAs can regulate the expression of various genes involved in DNA repair, including BRCA1, BRCA2, and ATM.

The positive regulation of double-strand break repair is essential for maintaining genome stability and preventing the development of disease. Defects in these pathways can lead to increased genomic instability, which is a hallmark of cancer and other genetic disorders. Therefore, understanding the mechanisms of positive regulation of double-strand break repair is crucial for developing new therapeutic strategies for treating these diseases.'
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Proteins (8)

Compounds (61)