Nibrin

Nibrin, also known as NBN or Nbs1, is a is_associated_with::protein which in humans is encoded by the NBN is_associated_with::gene.

Function
Nibrin is a protein associated with the repair of double strand breaks (DSBs) which pose serious damage to a genome. It is a 754 amino acid protein identified as a member of the NBS1/hMre11/RAD50(N/M/R, more commonly referred to as MRN) double strand DNA break repair complex. This complex recognizes DNA damage and rapidly relocates to DSB sites and forms nuclear foci. It also has a role in regulation of N/M/R (MRN) protein complex activity which includes end-processing of both physiological and mutagenic DNA double strand breaks (DSBs).

Cellular response to DSBs
Cellular response is performed by damage sensors, effectors of lesion repair and signal transduction. The central role is carried out by is_associated_with::ataxia telangiectasia mutated (ATM) by activating the DSB signaling cascade, phosphorylating downstream substrates such as histone is_associated_with::H2AX and NBS1. NBS1 relocates to DSB sites by interaction of FHA/BRCT domains with phosphorylated histone H2AX. Once it interacts with nibrin c-terminal his_associated_with::Mre11-binding domain, hMre11 and his_associated_with::Rad50 relocate from the cytoplasm to the nucleus then to sites of DSBs. They finally relocate to N/M/R where they form the foci at the site of damage.

Double strand breaks (DSBs)
DSBs occur during is_associated_with::V(D)J recombination during early B and is_associated_with::T cell development. This is at the point when the cells of the immune system are developing and the DSBs effect the development of lymphoid cells. DSBs also occur in immunoglobulin class switch in mature is_associated_with::B cells. More frequently, however, DSBs are caused by mutagenic agents like radiomimetic chemicals and ionizing radiation(IR).

DSB mutations
As mentioned, DSBs cause extreme damage to DNA. Mutations that cause defective repair of DSBs tend to accumulate un-repaired DSBs. One such mutation is associated with is_associated_with::Nijmegen breakage syndrome (NBS), a radiation hyper-sensitive disease. It is a rare inherited autosomal recessive condition of chrosomal instability. It has been linked to mutations within is_associated_with::exons 6-10 in the NBS1 gene which results in a truncated protein. Characteristics of NBS include is_associated_with::microcephaly, cranial characteristics, is_associated_with::growth retardation, impaired sexual maturation, is_associated_with::immunodeficiency/recurring infections and a predisposition to cancer. This predisposition to cancer may be linked to the DSBs occurring at the development of lymphoid cells.

Fertility
Two adult is_associated_with::siblings, both heterozygous for two particular NBS1 is_associated_with::nonsense mutations displayed cellular sensitivity to is_associated_with::radiation, is_associated_with::chromosome instability and fertility defects, but not the developmental defects that are typically found in other NBS patients. These individuals appear to be primarily defective in is_associated_with::homologous recombination, a process that accurately repairs double-strand breaks, both in is_associated_with::somatic cells and during is_associated_with::meiosis.

Orthologs of NBS1 have been studied in mice and the plant is_associated_with::Arabidopsis. NBS1 mutant mice display cellular radiation sensitivity and female mice are sterile due to oogenesis failure. Studies of NBS1 mutants in Arabidopsis revealed that NBS1 has a role in recombination during early stages of meiosis.

NBS1 over-expression in cancer
NBS1 has a role in is_associated_with::microhomology-mediated end joining (MMEJ) repair of double strand breaks. It is one of 6 enzymes required for this error prone DNA repair pathway. NBS1 is over-expressed in some prostate cancers, in head and neck cancer, and in squamous cell carcinoma of the oral cavity.

Cancers are very often deficient in expression of one or more DNA repair genes, but over-expression of a DNA repair gene is less usual in cancer. For instance, at least 36 DNA repair enzymes, when mutationally defective in germ line cells, cause increased risk of cancer (hereditary is_associated_with::cancer syndromes). (Also see is_associated_with::DNA repair-deficiency disorder.) Similarly, at least 12 DNA repair genes have frequently been found to be epigenetically repressed in one or more cancers. (See also Epigenetically reduced DNA repair and cancer.) Ordinarily, deficient expression of a DNA repair enzyme results in increased un-repaired DNA damages which, through replication errors (translesion synthesis), lead to mutations and cancer. However, NBS1 mediated MMEJ repair is highly inaccurate, so in this case, over-expression, rather than under-expression, apparently leads to cancer.

Interactions
Nibrin has been shown to interact with:


 * is_associated_with::Ataxia telangiectasia mutated,
 * is_associated_with::BRCA1,
 * is_associated_with::H2AFX,
 * is_associated_with::MRE11A,
 * is_associated_with::Rad50,    and
 * is_associated_with::TERF2