Nibrin
Encyclopedia
Nibrin, also known as NBN, is a protein
which in humans is encoded by the NBN gene
.
) 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).
/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.
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 cell
s. More frequently, however, DSBs are caused by mutagenic agents like radiomimetic chemicals and ionizing radiation(IR).
(NBS), a radiation hyper-sensitive disease. It is a rare inherited autosomal recessive condition of chrosomal instability. It has been linked to mutations within exon
s 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.
with MRE11A
, Ataxia telangiectasia mutated
, Rad50
, H2AFX
, TERF2
and BRCA1
.
Protein
Proteins are biochemical compounds consisting of one or more polypeptides typically folded into a globular or fibrous form, facilitating a biological function. A polypeptide is a single linear polymer chain of amino acids bonded together by peptide bonds between the carboxyl and amino groups of...
which in humans is encoded by the NBN gene
Gene
A gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...
.
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 MRNMre11-Rad50-Nbs1
The MRN complex is heterotrimeric protein complex consisting of Mre11, Rad50 and Nbs1. It is involved in DNA repair in mammals. Nbs1 is referred to as Nibrin. This complex recognizes DNA damage and rapidly relocates to DSB sites and forms nuclear foci. Its activity includes end-processing of...
) 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 FHAForkhead-associated domain
In molecular biology, the forkhead-associated domain is a phosphopeptide recognition domain found in many regulatory proteins. It displays specificity for phosphothreonine-containing epitopes but will also recognise phosphotyrosine with relatively high affinity...
/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 recombinationV(D)J recombination
VJ recombination, also known as somatic recombination, is a mechanism of genetic recombination in the early stages of immunoglobulin and T cell receptors production of the immune system...
during early B and T cell
T cell
T cells or T lymphocytes belong to a group of white blood cells known as lymphocytes, and play a central role in cell-mediated immunity. They can be distinguished from other lymphocytes, such as B cells and natural killer cells , by the presence of a T cell receptor on the cell surface. They are...
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
Immunoglobulin class switching
Immunoglobulin class switching is a biological mechanism that changes a B cell's production of antibody from one class to another, for example, from an isotype called IgM to an isotype called IgG...
in mature B cell
B cell
B cells are lymphocytes that play a large role in the humoral immune response . The principal functions of B cells are to make antibodies against antigens, perform the role of antigen-presenting cells and eventually develop into memory B cells after activation by antigen interaction...
s. 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. One such mutation is associated with Nijmegen breakage syndromeNijmegen breakage syndrome
Nijmegen breakage syndrome , also known as Berlin breakage syndrome and Seemanova syndrome, is a rare autosomal recessive congenital disorder causing chromosomal instability, probably as a result of a defect in the Double Holliday junction DNA repair mechanism.NBS1 codes for a protein that has two...
(NBS), a radiation hyper-sensitive disease. It is a rare inherited autosomal recessive condition of chrosomal instability. It has been linked to mutations within exon
Exon
An exon is a nucleic acid sequence that is represented in the mature form of an RNA molecule either after portions of a precursor RNA have been removed by cis-splicing or when two or more precursor RNA molecules have been ligated by trans-splicing. The mature RNA molecule can be a messenger RNA...
s 6-10 in the NBS1 gene which results in a truncated protein. Characteristics of NBS include microcephaly
Microcephaly
Microcephaly is a neurodevelopmental disorder in which the circumference of the head is more than two standard deviations smaller than average for the person's age and sex. Microcephaly may be congenital or it may develop in the first few years of life...
, cranial characteristics, growth retardation, impaired sexual maturation, immunodeficiency
Immunodeficiency
Immunodeficiency is a state in which the immune system's ability to fight infectious disease is compromised or entirely absent. Immunodeficiency may also decrease cancer immunosurveillance. Most cases of immunodeficiency are acquired but some people are born with defects in their immune system,...
/recurring infections and a predisposition to cancer. This predisposition to cancer may be linked to the DSBs occurring at the development of lymphoid cells.
Interactions
Nibrin has been shown to interactProtein-protein interaction
Protein–protein interactions occur when two or more proteins bind together, often to carry out their biological function. Many of the most important molecular processes in the cell such as DNA replication are carried out by large molecular machines that are built from a large number of protein...
with MRE11A
MRE11A
Double-strand break repair protein MRE11A is a protein that in humans is encoded by the MRE11A gene.-Interactions:MRE11A has been shown to interact with Ku70, Ataxia telangiectasia mutated, MDC1, Rad50, Nibrin, TERF2 and BRCA1.-Further reading:...
, Ataxia telangiectasia mutated
Ataxia telangiectasia mutated
Ataxia telangiectasia mutated is a serine/threonine protein kinase that is recruited and activated by DNA double-strand breaks. It phosphorylates several key proteins that initiate activation of the DNA damage checkpoint, leading to cell cycle arrest, DNA repair or apoptosis...
, Rad50
RAD50
Rad50 may refer to:* RADIX-50, a character encoding scheme in computing* RAD50 , in biology, encodes a DNA repair protein involved in DNA double-strand break repair...
, H2AFX
H2AFX
H2AX is one of several genes coding for histone H2A. In humans and other eukaryotes, the DNA is wrapped around histone-groups, consisting of core histones H2A, H2B, H3 and H4. Thus, the H2AX contributes to the histone-formation and therefore the structure of DNA.H2AX becomes phosphorylated on...
, TERF2
TERF2
Telomeric repeat-binding factor 2 is a protein that is also known as TRF2 and TRBF2. It is in humans encoded by the TERF2 gene.-Interactions:...
and BRCA1
BRCA1
BRCA1 is a human caretaker gene that produces a protein called breast cancer type 1 susceptibility protein, responsible for repairing DNA. The first evidence for the existence of the gene was provided by the King laboratory at UC Berkeley in 1990...
.