|Symbols||; AT-V1; AT-V2; ATV; NBS; NBS1; P95|
|RNA expression pattern|
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 ataxia telangiectasia mutated (ATM) by activating the DSB signaling cascade, phosphorylating downstream substrates such as histone 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 hMre11-binding domain, hMre11 and hRad50 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 V(D)J recombination during early B and 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 B cells. More frequently, however, DSBs are caused by mutagenic agents like radiomimetic chemicals and ionizing radiation(IR).
As mentioned, DSBs cause extreme damage to DNA. One such mutation 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 exons 6-10 in the NBS1 gene which results in a truncated protein. Characteristics of NBS include microcephaly, cranial characteristics, growth retardation, impaired sexual maturation, 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.
NBS1 over-expression in cancer
NBS1 has a role in 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 cancer syndromes). (Also see 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.
Nibrin has been shown to interact with:
- "Entrez Gene: Nibrin".
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- Molecular Biology
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- GeneReviews/NCBI/NIH/UW entry on Nijmegen Breakage Syndrome
- nibrin protein, human at the US National Library of Medicine Medical Subject Headings (MeSH)