p95/NBS1

Domain

The FHA and BRCT domains are likely to have a crucial role for both binding to histone H2AX and for relocalization of MRE11/RAD50 complex to the vicinity of DNA damage.

The C-terminal domain contains a MRE11-binding site, and this interaction is required for the nuclear localization of the MRN complex.

The EEXXXDDL motif at the C-terminus is required for the interaction with ATM and its recruitment to sites of DNA damage and promote the phosphorylation of ATM substrates, leading to the events of DNA damage response.

Function

Component of the MRE11-RAD50-NBN (MRN complex) which plays a critical role in the cellular response to DNA damage and the maintenance of chromosome integrity. The complex is involved in double-strand break (DSB) repair, DNA recombination, maintenance of telomere integrity, cell cycle checkpoint control and meiosis. The complex possesses single-strand endonuclease activity and double-strand-specific 3'-5' exonuclease activity, which are provided by MRE11. RAD50 may be required to bind DNA ends and hold them in close proximity. NBN modulate the DNA damage signal sensing by recruiting PI3/PI4-kinase family members ATM, ATR, and probably DNA-PKcs to the DNA damage sites and activating their functions. It can also recruit MRE11 and RAD50 to the proximity of DSBs by an interaction with the histone H2AX. NBN also functions in telomere length maintenance by generating the 3' overhang which serves as a primer for telomerase dependent telomere elongation. NBN is a major player in the control of intra-S-phase checkpoint and there is some evidence that NBN is involved in G1 and G2 checkpoints. The roles of NBS1/MRN encompass DNA damage sensor, signal transducer, and effector, which enable cells to maintain DNA integrity and genomic stability. Forms a complex with RBBP8 to link DNA double-strand break sensing to resection. Enhances AKT1 phosphorylation possibly by association with the mTORC2 complex.

Involvement in disease

Nijmegen breakage syndrome

NBS

A disorder characterized by chromosomal instability, radiation sensitivity, microcephaly, growth retardation, immunodeficiency and predisposition to cancer, particularly to lymphoid malignancies.

None

The disease is caused by variants affecting the gene represented in this entry.

Breast cancer

BC

A common malignancy originating from breast epithelial tissue. Breast neoplasms can be distinguished by their histologic pattern. Invasive ductal carcinoma is by far the most common type. Breast cancer is etiologically and genetically heterogeneous. Important genetic factors have been indicated by familial occurrence and bilateral involvement. Mutations at more than one locus can be involved in different families or even in the same case.

None

Disease susceptibility is associated with variants affecting the gene represented in this entry.

Aplastic anemia

AA

A form of anemia in which the bone marrow fails to produce adequate numbers of peripheral blood elements. It is characterized by peripheral pancytopenia and marrow hypoplasia.

None

Disease susceptibility may be associated with variants affecting the gene represented in this entry.

Defects in NBN might play a role in the pathogenesis of childhood acute lymphoblastic leukemia (ALL).

Post-translational modifications

Phosphorylated by ATM in response of ionizing radiation, and such phosphorylation is responsible intra-S phase checkpoint control and telomere maintenance.

Tissue specificity

Ubiquitous. Expressed at high levels in testis.

Cellular localization

• Nucleus
• Nucleus
• PML body
• Chromosome
• Telomere
• Chromosome
• Localizes to discrete nuclear foci after treatment with genotoxic agents.

Alternative names

• Nibrin
• Cell cycle regulatory protein p95
• Nijmegen breakage syndrome protein 1
• NBN
• NBS
• NBS1
• P95

Database links

• entrezGene:4683
• omim:602667
• swissprot:O60934

Target type

Proteins

Primary research area

Oncology

Molecular weight

84959Da