negative regulation of double-strand break repair via homologous recombination

Definition

Target type: biologicalprocess

Any process that stops, prevents, or reduces the frequency, rate or extent of double-strand break repair via homologous recombination. [GOC:vw]

Negative regulation of double-strand break repair via homologous recombination is a crucial process that ensures proper maintenance of genomic integrity. This intricate pathway involves a series of tightly controlled steps that aim to suppress or fine-tune the activity of homologous recombination (HR), a major DNA repair mechanism. HR is essential for repairing double-strand breaks (DSBs), which are highly deleterious DNA lesions that can lead to chromosomal instability, mutations, and ultimately, cell death. While HR is generally beneficial, excessive or inappropriate activation of this pathway can have detrimental consequences. Therefore, cells have evolved elaborate mechanisms to precisely regulate HR to prevent its dysregulation.

One key regulatory layer involves modulating the availability and activity of key HR proteins. For instance, the BRCA2 protein, a central player in HR, is subject to post-translational modifications like phosphorylation and ubiquitination. These modifications can alter its stability, localization, and interaction with other proteins, influencing its role in HR. Similarly, the RAD51 recombinase, a critical enzyme in HR, is regulated by its interaction with other proteins, such as RAD52, which helps load it onto single-stranded DNA during HR.

Another important aspect of HR regulation involves controlling the initiation and progression of the HR process. For example, the MRN complex (MRE11-RAD50-NBS1) plays a critical role in sensing DSBs and initiating the HR cascade. The activity of this complex can be regulated by factors like ATM kinase, which phosphorylates MRN components, promoting its activity and activating downstream signaling pathways.

Furthermore, HR can be negatively regulated by competing DNA repair pathways. For example, non-homologous end joining (NHEJ), another major DNA repair pathway, can suppress HR by directly competing for DSBs. In some cases, NHEJ can even interfere with HR by degrading intermediates involved in the HR process.

Moreover, cells utilize specialized mechanisms to block HR in specific contexts. For instance, during meiosis, HR is tightly controlled to ensure proper chromosome pairing and segregation. This regulation involves specialized proteins that can restrict HR activity to specific regions of the genome, preventing inappropriate recombination events.

In summary, negative regulation of double-strand break repair via homologous recombination is a multifaceted process involving a complex interplay of proteins and pathways. This regulation ensures that HR operates within a controlled window, minimizing its potential harmful consequences and maintaining genomic stability. Understanding this regulatory network is crucial for comprehending the intricate mechanisms of DNA repair and its implications for human health and disease.'
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Proteins (8)

Compounds (389)