Nibrin, also known as NBN or NBS1, is a
protein
Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, respo ...
which in humans is encoded by the ''NBN''
gene
In biology, the word gene (from , ; "...Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a ba ...
.
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
ataxia telangiectasia mutated
ATM serine/threonine kinase or Ataxia-telangiectasia mutated, symbol ATM, 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 ...
(ATM) by activating the DSB signaling cascade, phosphorylating downstream substrates such as histone
H2AX
H2A histone family member X (usually abbreviated as H2AX) is a type of histone protein from the H2A family encoded by the ''H2AFX'' gene. An important phosphorylated form is γH2AX (S139), which forms when double-strand breaks appear.
In humans ...
and NBS1. NBS1 relocates to DSB sites by interaction of
FHA/BRCT domains with phosphorylated histone H2AX. Once it interacts with nibrin c-terminal h
Mre11
Double-strand break repair protein MRE11 is an enzyme that in humans is encoded by the ''MRE11'' gene. The gene has been designated ''MRE11A'' to distinguish it from the pseudogene ''MRE11B'' that is nowadays named ''MRE11P1''.
Function
This ge ...
-binding domain, hMre11 and h
Rad50
DNA repair protein RAD50, also known as RAD50, is a protein that in humans is encoded by the ''RAD50'' gene.
Function
The protein encoded by this gene is highly similar to ''Saccharomyces cerevisiae'' Rad50, a protein involved in DNA double- ...
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
V(D)J recombination is the mechanism of somatic recombination that occurs only in developing lymphocytes during the early stages of T and B cell maturation. It results in the highly diverse repertoire of antibodies/immunoglobulins and T cell rece ...
during early B and
T cell
A T cell is a type of lymphocyte. T cells are one of the important white blood cells of the immune system and play a central role in the adaptive immune response. T cells can be distinguished from other lymphocytes by the presence of a T-cell r ...
development. This is at the point when the cells of the immune system are developing and the DSBs affect the development of lymphoid cells. DSBs also occur in
immunoglobulin class switch in mature
B cell
B cells, also known as B lymphocytes, are a type of white blood cell of the lymphocyte subtype. They function in the humoral immunity component of the adaptive immune system. B cells produce antibody molecules which may be either secreted or ...
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. Mutations that cause defective repair of DSBs tend to accumulate un-repaired DSBs. 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
exon
An exon is any part of a gene that will form a part of the final mature RNA produced by that gene after introns have been removed by RNA splicing. The term ''exon'' refers to both the DNA sequence within a gene and to the corresponding sequen ...
s 6–10 in the NBS1 gene which results in a truncated protein.
Characteristics of NBS include
microcephaly
Microcephaly (from New Latin ''microcephalia'', from Ancient Greek μικρός ''mikrós'' "small" and κεφαλή ''kephalé'' "head") is a medical condition involving a smaller-than-normal head. Microcephaly may be present at birth or it ...
, cranial characteristics,
growth retardation
Delayed milestone, also called developmental delays, is used to describe the condition where a child does not reach one of these stages at the expected age. However, in most cases, a wide variety of ages can be considered normal, and not a cause fo ...
, impaired sexual maturation,
immunodeficiency
Immunodeficiency, also known as immunocompromisation, is a state in which the immune system's ability to fight infectious diseases and cancer is compromised or entirely absent. Most cases are acquired ("secondary") due to extrinsic factors that a ...
/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
sibling
A sibling is a relative that shares at least one parent with the subject. A male sibling is a brother and a female sibling is a sister. A person with no siblings is an only child.
While some circumstances can cause siblings to be raised separat ...
s, both
heterozygous
Zygosity (the noun, zygote, is from the Greek "yoked," from "yoke") () is the degree to which both copies of a chromosome or gene have the same genetic sequence. In other words, it is the degree of similarity of the alleles in an organism.
Mo ...
for two particular NBS1
nonsense mutation
In genetics, a nonsense mutation is a point mutation in a sequence of DNA that results in a premature stop codon, or a ''nonsense codon'' in the transcribed mRNA, and in leading to a truncated, incomplete, and usually nonfunctional protein produc ...
s displayed cellular sensitivity to
radiation
In physics, radiation is the emission or transmission of energy in the form of waves or particles through space or through a material medium. This includes:
* ''electromagnetic radiation'', such as radio waves, microwaves, infrared, visi ...
,
chromosome instability
Chromosomal instability (CIN) is a type of genomic instability in which chromosomes are unstable, such that either whole chromosomes or parts of chromosomes are duplicated or deleted. More specifically, CIN refers to the increase in rate of additio ...
and
fertility defects, but not the
developmental
Development of the human body is the process of growth to maturity. The process begins with fertilization, where an egg released from the ovary of a female is penetrated by a sperm cell from a male. The resulting zygote develops through mitosi ...
defects that are typically found in other NBS patients.
These individuals appear to be primarily defective in
homologous recombination
Homologous recombination is a type of genetic recombination in which genetic information is exchanged between two similar or identical molecules of double-stranded or single-stranded nucleic acids (usually DNA as in cellular organisms but may ...
, a process that accurately repairs double-strand breaks, both in
somatic cell
A somatic cell (from Ancient Greek σῶμα ''sôma'', meaning "body"), or vegetal cell, is any biological cell forming the body of a multicellular organism other than a gamete, germ cell, gametocyte or undifferentiated stem cell. Such cells compo ...
s and during
meiosis
Meiosis (; , since it is a reductional division) is a special type of cell division of germ cells in sexually-reproducing organisms that produces the gametes, such as sperm or egg cells. It involves two rounds of division that ultimately resu ...
.
Orthologs
Sequence homology is the biological homology between DNA, RNA, or protein sequences, defined in terms of shared ancestry in the evolutionary history of life. Two segments of DNA can have shared ancestry because of three phenomena: either a spec ...
of NBS1 have been studied in mice
and the plant
arabidopsis
''Arabidopsis'' (rockcress) is a genus in the family Brassicaceae. They are small flowering plants related to cabbage and mustard. This genus is of great interest since it contains thale cress (''Arabidopsis thaliana''), one of the model organi ...
.
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
microhomology-mediated end joining
Microhomology-mediated end joining (MMEJ), also known as alternative nonhomologous end-joining (Alt-NHEJ) is one of the pathways for repairing double-strand breaks in DNA. As reviewed by McVey and Lee, the foremost distinguishing property of MMEJ ...
(MMEJ) repair of double strand breaks. It is one of 6 enzymes required for this error prone DNA repair pathway.
NBS1 is often over-expressed in prostate cancer,
in liver cancer,
in esophageal squamous cell carcinoma,
in non-small cell lung carcinoma, hepatoma, and esophageal cancer,
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 syndrome
A cancer syndrome, or family cancer syndrome, is a genetic disorder in which inherited genetic mutations in one or more genes predispose the affected individuals to the development of cancers and may also cause the early onset of these cancers. Ca ...
s). (Also see
DNA repair-deficiency disorder
A DNA repair-deficiency disorder is a medical condition due to reduced functionality of DNA repair.
DNA repair defects can cause an accelerated aging disease or an increased risk of cancer, or sometimes both.
DNA repair defects and accelerated a ...
.) 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
DNA repair is a collection of processes by which a cell identifies and corrects damage to the DNA molecules that encode its genome. In human cells, both normal metabolic activities and environmental factors such as radiation can cause DNA dama ...
), 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.
Herpes virus
HSV-1
Herpes simplex virus 1 and 2 (HSV-1 and HSV-2), also known by their taxonomical names ''Human alphaherpesvirus 1'' and '' Human alphaherpesvirus 2'', are two members of the human ''Herpesviridae'' family, a set of viruses that produce viral inf ...
infects more than 90% of adults over the age of 50.
Alphaherpesviruses alone can cause the host to have mild symptoms, but these
viruses
A virus is a submicroscopic infectious agent that replicates only inside the living cells of an organism. Viruses infect all life forms, from animals and plants to microorganisms, including bacteria and archaea.
Since Dmitri Ivanovsky's 1 ...
can be associated with severe disease when they are transferred to a new species. Humans can even pass and also get an
HSV-1
Herpes simplex virus 1 and 2 (HSV-1 and HSV-2), also known by their taxonomical names ''Human alphaherpesvirus 1'' and '' Human alphaherpesvirus 2'', are two members of the human ''Herpesviridae'' family, a set of viruses that produce viral inf ...
infection from other primate species. However, because of evolutionary differences between primate species, only some species can pass HSV-1 in an interspecies interaction. Also, though HSV-1 transmission from humans to other species primates can occur, there is no known sustained transmission chains that have resulted from constant transmission. A study found that Nbs1 is the most diverged in DNA sequence in the
MRN complex
The MRN complex (MRX complex in yeast) is a protein complex consisting of Mre11, Rad50 and Nbs1 (also known as Nibrin in humans and as Xrs2 in yeast). In eukaryotes, the MRN/X complex plays an important role in the initial processing of double-st ...
between different primate species and that there is a high degree of species specificity, causing variability in promotion of the HSV-1 life cycle. The same study found that Nbs1 interacts with HSV-1's
ICP0
Human Herpes Virus (HHV) Infected Cell Polypeptide 0 (ICP0) is a protein, encoded by the DNA of herpes viruses. It is produced by herpes viruses during the earliest stage of infection, when the virus has recently entered the host cell; this stage ...
proteins in an area of structural disorder of the nibrin. This suggests that in general, viruses commonly interact in intrinsically disordered domains in host proteins. It is possible that there are differences in the mammalian genomes that create unique environments for the viruses. Host proteins that are specific to the species might determine how the viruses must adapt to be able to ignite an infection in a new species. The evolution of increased disorder in nibrin benefits the host in decreasing ICP0 interaction and virus hijack. Nbs1 may not be the only host protein that evolves this way.
HSV-1-infection has been shown to result from the phosphorylation of Nbs1. It has been shown in studies that activation of the MRN complex and ATM biochemical cascade is consistent for a resulting HSV-1 infection. When there is an HSV-1 infection, the nucleus is reorganized causing the formation of RCs (replication compartments) where gene expression and DNA replication occurs. Proteins in the host used for DNA repair and damage response are needed for virus production.
ICP8 ICP8, the herpes simplex virus type-1 single-strand DNA-binding protein, is one of seven proteins encoded in the viral genome of HSV-1 that is required for HSV-1 DNA replication. It is able to anneal to single-stranded DNA ( ssDNA) as well as melt ...
, which is a viral single-strand binding protein, is known to interact with several DNA repair proteins, such as
Rad50
DNA repair protein RAD50, also known as RAD50, is a protein that in humans is encoded by the ''RAD50'' gene.
Function
The protein encoded by this gene is highly similar to ''Saccharomyces cerevisiae'' Rad50, a protein involved in DNA double- ...
,
Mre11
Double-strand break repair protein MRE11 is an enzyme that in humans is encoded by the ''MRE11'' gene. The gene has been designated ''MRE11A'' to distinguish it from the pseudogene ''MRE11B'' that is nowadays named ''MRE11P1''.
Function
This ge ...
,
BRG1
Transcription activator BRG1 also known as ATP-dependent chromatin remodeler SMARCA4 is a protein that in humans is encoded by the ''SMARCA4'' gene.
Function
The protein encoded by this gene is a member of the SWI/SNF family of proteins and i ...
, and
DNA-PKcs
DNA-dependent protein kinase, catalytic subunit, also known as DNA-PKcs, is an enzyme that in humans is encoded by the gene designated as ''PRKDC'' or ''XRCC7''. DNA-PKcs belongs to the phosphatidylinositol 3-kinase-related kinase protein family. ...
. Ul12 and ICP8 viral proteins function together as a
recombinase
Recombinases are genetic recombination enzymes.
Site specific recombinases
DNA recombinases are widely used in multicellular organisms to manipulate the structure of genomes, and to control gene expression. These enzymes, derived from bacteria (b ...
, possibly showing that while working with the host's recombination factors, work to form a
concatemer
A concatemer is a long continuous DNA molecule that contains multiple copies of the same DNA sequence linked in series. These polymeric molecules are usually copies of an entire genome linked end to end and separated by ''cos'' sites (a protein bi ...
by stimulating
homologous recombination
Homologous recombination is a type of genetic recombination in which genetic information is exchanged between two similar or identical molecules of double-stranded or single-stranded nucleic acids (usually DNA as in cellular organisms but may ...
. These proteins may move the MRN complex towards the viral genome so it is able to promote homologous recombination, and to prevent
non-homologous recombination
Illegitimate recombination, or nonhomologous recombination, is the process by which two unrelated double stranded segments of DNA are joined. This insertion of genetic material which is not meant to be adjacent tends to lead to genes being broken ...
as non-homologous recombination can have anti-viral effects. This possibly shows that the reaction between UL12 and MRN regulates the complex in a way that benefits the herpes virus.
[Nandakumar Balasubramanian, Ping Bai, Gregory Buchek, George Korza and Sandra K. Weller (December 2010). “Physical Interaction between the Herpes Simplex Virus Type 1 Exonuclease, UL12, and the DNA Double-Strand Break-Sensing MRN Complex.” J. Virol. 84 (24): 12504-12514. https://dx.doi.org/10.1128/JVI.01506-10]
Interactions
Nibrin has been shown to
interact
Advocates for Informed Choice, dba interACT or interACT Advocates for Intersex Youth, is a 501(c)(3) nonprofit organization using innovative strategies to advocate for the legal and human rights of children with intersex traits. The organizati ...
with:
*
Ataxia telangiectasia mutated
ATM serine/threonine kinase or Ataxia-telangiectasia mutated, symbol ATM, 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 ...
,
* BRCA1
Breast cancer type 1 susceptibility protein is a protein that in humans is encoded by the ''BRCA1'' () gene. Orthologs are common in other vertebrate species, whereas invertebrate genomes may encode a more distantly related gene. ''BRCA1'' is a h ...
,
* H2AFX
H2A histone family member X (usually abbreviated as H2AX) is a type of histone protein from the H2A family encoded by the ''H2AFX'' gene. An important phosphorylated form is γH2AX (S139), which forms when double-strand breaks appear.
In humans ...
,
* MRE11A
Double-strand break repair protein MRE11 is an enzyme that in humans is encoded by the ''MRE11'' gene. The gene has been designated ''MRE11A'' to distinguish it from the pseudogene ''MRE11B'' that is nowadays named ''MRE11P1''.
Function
This ge ...
,
* Rad50
DNA repair protein RAD50, also known as RAD50, is a protein that in humans is encoded by the ''RAD50'' gene.
Function
The protein encoded by this gene is highly similar to ''Saccharomyces cerevisiae'' Rad50, a protein involved in DNA double- ...
,[ and
* ]TERF2
Telomeric repeat-binding factor 2 is a protein that is present at telomeres throughout the cell cycle. It is also known as TERF2, TRF2, and TRBF2, and is encoded in humans by the ''TERF2'' gene. It is a component of the shelterin nucleoprotein co ...
References
Further reading
*
*
*
*
External links
GeneReviews/NCBI/NIH/UW entry on Nijmegen Breakage Syndrome
* {{MeshName, nibrin+protein,+human
Proteins