RAD51

HR proteins conserved domains

RAD51 is a protein that plays a crucial role in the process of homologous recombination, a mechanism of DNA repair that is essential for maintaining the integrity of the genome and for the accurate repair of DNA double-strand breaks. RAD51 is highly conserved across species, indicating its vital role in cellular processes. This protein is encoded by the RAD51 gene in humans.

Function

RAD51 is involved in the search for homology and strand pairing stages of the homologous recombination process. It forms a nucleoprotein filament on DNA that is instrumental in the search for the homologous DNA sequence and the subsequent DNA strand invasion process. This action facilitates the repair of DNA double-strand breaks, which can be caused by radiation, chemicals, and during replication stress. The proper function of RAD51 is critical for maintaining genomic stability and preventing the accumulation of DNA damage, which can lead to cancer.

Mechanism

The mechanism of RAD51 in homologous recombination involves several steps. Initially, the RAD51 protein binds to single-stranded DNA (ssDNA) at the site of a break. With the help of accessory proteins, such as RAD52 and the RAD51 paralogs, RAD51 forms a filament on the ssDNA. This filament then searches for and invades a homologous DNA duplex, forming a D-loop structure that allows for the exchange and repair of genetic information. The successful completion of this process results in the accurate repair of the DNA double-strand break.

Clinical Significance

Mutations in the RAD51 gene or dysregulation of RAD51 protein function can lead to genomic instability and predispose individuals to cancer. For example, defects in RAD51 have been associated with an increased risk of developing breast and ovarian cancers. Furthermore, the RAD51 protein is a target for cancer therapy, as inhibiting RAD51 function can sensitize cancer cells to DNA-damaging agents, making it a potential therapeutic target in oncology.

Regulation

The activity and function of RAD51 are tightly regulated by various post-translational modifications and interactions with other proteins. Phosphorylation, for example, can modulate the activity of RAD51, affecting its ability to bind DNA and perform its function in homologous recombination. Additionally, proteins such as BRCA2 play a crucial role in regulating RAD51, by directing its binding to sites of DNA damage and facilitating the formation of the RAD51 nucleoprotein filament.

Evolution

The RAD51 protein is highly conserved across eukaryotes, highlighting its fundamental role in DNA repair and genomic maintenance. Homologs of RAD51 have been identified in a wide range of organisms, from yeast (where it is known as Rad51) to humans, indicating the evolutionary importance of homologous recombination in cellular survival and genome integrity.

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