MSX-2

MRE11

The MRE11 gene encodes a protein that is a crucial component of the MRN complex, which plays a significant role in the maintenance of genomic stability. The MRN complex, consisting of MRE11, RAD50, and NBS1, is essential for the detection and repair of DNA double-strand breaks (DSBs), a type of DNA damage that can lead to genomic instability and cancer if not properly repaired.

Structure and Function

The MRE11 protein is characterized by its nuclease activity, which is vital for the processing of DNA ends during repair. It possesses both 3' to 5' exonuclease and endonuclease activities, allowing it to resect DNA ends to facilitate homologous recombination, a precise DNA repair mechanism.

MRE11, along with RAD50 and NBS1, forms the MRN complex, which is involved in several key processes:

• DNA Damage Sensing: The MRN complex is one of the first responders to DNA double-strand breaks. It binds to the broken DNA ends and recruits other proteins involved in the DNA damage response.
• DNA End Resection: MRE11's nuclease activity is crucial for processing DNA ends to generate single-stranded DNA, which is necessary for the recruitment of RAD51 and the initiation of homologous recombination.
• Activation of ATM Kinase: The MRN complex is involved in the activation of the ATM kinase, a critical regulator of the DNA damage response. ATM phosphorylates several downstream targets that lead to cell cycle arrest and DNA repair.

Clinical Significance

Mutations in the MRE11 gene can lead to genomic instability and are associated with several human diseases, including:

• Ataxia-Telangiectasia-Like Disorder (ATLD): A rare genetic disorder caused by mutations in the MRE11 gene, characterized by progressive cerebellar ataxia, oculocutaneous telangiectasia, and increased cancer risk.
• Cancer: Defects in the MRN complex, including MRE11, have been implicated in various cancers due to their role in maintaining genomic integrity.

Research and Therapeutic Implications

Understanding the function of MRE11 and the MRN complex is crucial for developing targeted therapies for diseases associated with DNA repair defects. Inhibitors of the MRN complex are being explored as potential cancer therapies, particularly in tumors with existing DNA repair deficiencies.

Also see

• DNA Repair
• Homologous Recombination
• ATM Kinase
• RAD50
• NBS1
• Genomic Instability