NCBI

Nibrin
Identifiers
Symbol	?
HGNC	7668
OMIM	602667
PDB	3Q96
RefSeq	NM_002485
UniProt	O60934
Search for Structures Swiss-model Domains InterPro

Nibrin (NBS1) is a protein encoded by the NBS1 gene in humans. It is a crucial component of the MRN complex, which plays a significant role in the repair of DNA double-strand breaks (DSBs) through the homologous recombination and non-homologous end joining pathways. Nibrin is essential for maintaining genomic stability and preventing genomic instability that can lead to cancer.

Structure

Nibrin is a 754 amino acid protein with several important domains that facilitate its function in DNA repair. The N-terminal region contains a forkhead-associated (FHA) domain and two BRCA1 C-terminal (BRCT) domains, which are involved in protein-protein interactions. These domains are critical for the recruitment of Nibrin to sites of DNA damage.

Function

Nibrin is a part of the MRN complex, which also includes MRE11 and RAD50. This complex is involved in the detection and repair of DNA double-strand breaks. Nibrin acts as a mediator that recruits the MRN complex to DNA damage sites and facilitates the activation of ATM kinase, a key regulator of the DNA damage response.

Role in DNA Repair

The MRN complex, with Nibrin as a component, is involved in the initial recognition of DNA double-strand breaks. Nibrin's interaction with ATM kinase is crucial for the phosphorylation of several downstream targets involved in cell cycle checkpoints and DNA repair processes.

Cell Cycle Regulation

Nibrin also plays a role in cell cycle regulation. It is involved in the activation of the S-phase checkpoint, which prevents the replication of damaged DNA. This function is critical for maintaining genomic integrity during cell division.

Clinical Significance

Mutations in the NBS1 gene can lead to Nijmegen breakage syndrome, a rare autosomal recessive disorder characterized by microcephaly, growth retardation, immunodeficiency, and a predisposition to cancer. Patients with this syndrome exhibit increased sensitivity to ionizing radiation and a high incidence of lymphoid malignancies.

Research and Therapeutic Implications

Understanding the function of Nibrin and the MRN complex is crucial for developing targeted therapies for cancer treatment. Inhibitors of the MRN complex or its interactions with ATM kinase are being explored as potential therapeutic strategies to sensitize cancer cells to DNA-damaging agents.

Also see

• MRN complex
• DNA repair
• ATM kinase
• Nijmegen breakage syndrome
• Genomic instability