Non-homologous end joining

Non-homologous end joining (NHEJ)

is a pathway that repairs double-strand
breaks in DNA. NHEJ is referred to as
"non-homologous" because the break
ends are directly ligated without the need
for a homologous template, in contrast to
homology directed repair, which requires
a homologous sequence to guide repair.
The term "non-homologous end joining"
was coined in 1996 by Moore and
Haber.[1]

NHEJ is typically guided by short

homologous DNA sequences called
microhomologies. These
microhomologies are often present in
single-stranded overhangs on the ends of
double-strand breaks. When the
overhangs are perfectly compatible,
NHEJ usually repairs the break
accurately.[1][2][3][4] Imprecise repair
leading to loss of nucleotides can also
occur, but is much more common when
the overhangs are not compatible.
Inappropriate NHEJ can lead to
translocations and telomere fusion,
hallmarks of tumor cells.[5]
Non-homologous end joining (NHEJ) and homologous recombination
NHEJ implementations are understood to (HR) in mammals during DNA double-strand break
have been existent throughout nearly all
biological systems and it is the
predominant double-strand break repair pathway in mammalian cells.[6] In budding yeast (Saccharomyces
cerevisiae), however, homologous recombination dominates when the organism is grown under common
laboratory conditions.

When the NHEJ pathway is inactivated, double-strand breaks can be repaired by a more error-prone pathway
called microhomology-mediated end joining (MMEJ). In this pathway, end resection reveals short
microhomologies on either side of the break, which are then aligned to guide repair.[7] This contrasts with
classical NHEJ, which typically uses microhomologies already exposed in single-stranded overhangs on the
DSB ends. Repair by MMEJ therefore leads to deletion of the DNA sequence between the microhomologies.

Contents
In bacteria
In eukaryotes
End binding and tethering
 End processing
Ligation
Other
Regulation
V(D)J recombination
At telomeres
Consequences of dysfunction
Aging
List of proteins involved in NHEJ in human cells
References

In bacteria
Many species of bacteria, including Escherichia coli, lack an end joining pathway and thus rely completely on
homologous recombination to repair double-strand breaks. NHEJ proteins have been identified in a number of
bacteria, however, including Bacillus subtilis, Mycobacterium tuberculosis, and Mycobacterium
smegmatis.[8][9] Bacteria utilize a remarkably compact version of NHEJ in which all of the required activities
are contained in only two proteins: a Ku homodimer and the multifunctional ligase/polymerase/nuclease
LigD.[10] In mycobacteria, NHEJ is much more error prone than in yeast, with bases often added to and
deleted from the ends of double-strand breaks during repair.[9] Many of the bacteria that possess NHEJ
proteins spend a significant portion of their life cycle in a stationary haploid phase, in which a template for
recombination is not available.[8] NHEJ may have evolved to help these organisms survive DSBs induced
during desiccation.[11] Corndog and Omega, two related mycobacteriophages of Mycobacterium smegmatis,
also encode Ku homologs and exploit the NHEJ pathway to recircularize their genomes during infection.[12]
Unlike homologous recombination, which has been studied extensively in bacteria, NHEJ was originally
discovered in eukaryotes and was only identified in prokaryotes in the past decade.

In eukaryotes
In contrast to bacteria, NHEJ in eukaryotes utilizes a number of proteins, which participate in the following
steps:

End binding and tethering

In yeast, the Mre11-Rad50-Xrs2 (MRX) complex is recruited to DSBs early and is thought to promote
bridging of the DNA ends.[13] The corresponding mammalian complex of Mre11-Rad50-Nbs1 (MRN) is also
involved in NHEJ, but it may function at multiple steps in the pathway beyond simply holding the ends in
proximity.[14] DNA-PKcs is also thought to participate in end bridging during mammalian NHEJ.[15]

Eukaryotic Ku is a heterodimer consisting of Ku70 and Ku80, and forms a complex with DNA-PKcs, which
is present in mammals but absent in yeast. Ku is a basket-shaped molecule that slides onto the DNA end and
translocates inward. Ku may function as a docking site for other NHEJ proteins, and is known to interact with
the DNA ligase IV complex and XLF.[16][17]

End processing
End processing involves removal of damaged or mismatched nucleotides by nucleases and resynthesis by
DNA polymerases. This step is not necessary if the ends are already compatible and have 3' hydroxyl and 5'
phosphate termini.

Little is known about the function of nucleases in NHEJ. Artemis is required for opening the hairpins that are
formed on DNA ends during V(D)J recombination, a specific type of NHEJ, and may also participate in end
trimming during general NHEJ.[18] Mre11 has nuclease activity, but it seems to be involved in homologous
recombination, not NHEJ.

The X family DNA polymerases Pol λ and Pol μ (Pol4 in yeast) fill gaps during NHEJ.[3][19][20] Yeast
lacking Pol4 are unable to join 3' overhangs that require gap filling, but remain proficient for gap filling at 5'
overhangs.[21] This is because the primer terminus used to initiate DNA synthesis is less stable at 3' overhangs,
necessitating a specialized NHEJ polymerase.

Ligation

The DNA ligase IV complex, consisting of the catalytic subunit DNA ligase IV and its cofactor XRCC4
(Dnl4 and Lif1 in yeast), performs the ligation step of repair.[22] XLF, also known as Cernunnos, is
homologous to yeast Nej1 and is also required for NHEJ.[23][24] While the precise role of XLF is unknown, it
interacts with the XRCC4/DNA ligase IV complex and likely participates in the ligation step.[25] Recent
evidence suggests that XLF promotes re-adenylation of DNA ligase IV after ligation, recharging the ligase and
allowing it to catalyze a second ligation.[26]

Other

In yeast, Sir2 was originally identified as an NHEJ protein, but is now known to be required for NHEJ only
because it is required for the transcription of Nej1.[27]

Regulation
The choice between NHEJ and homologous recombination for repair of a double-strand break is regulated at
the initial step in recombination, 5' end resection. In this step, the 5' strand of the break is degraded by
nucleases to create long 3' single-stranded tails. DSBs that have not been resected can be rejoined by NHEJ,
but resection of even a few nucleotides strongly inhibits NHEJ and effectively commits the break to repair by
recombination.[20] NHEJ is active throughout the cell cycle, but is most important during G1 when no
homologous template for recombination is available. This regulation is accomplished by the cyclin-dependent
kinase Cdk1 (Cdc28 in yeast), which is turned off in G1 and expressed in S and G2. Cdk1 phosphorylates the
nuclease Sae2, allowing resection to initiate.[28]

V(D)J recombination
NHEJ plays a critical role in V(D)J recombination, the process by which B-cell and T-cell receptor diversity is
generated in the vertebrate immune system.[29] In V(D)J recombination, hairpin-capped double-strand breaks
are created by the RAG1/RAG2 nuclease, which cleaves the DNA at recombination signal sequences.[30]
These hairpins are then opened by the Artemis nuclease and joined by NHEJ.[18] A specialized DNA
polymerase called terminal deoxynucleotidyl transferase (TdT), which is only expressed in lymph tissue, adds
nontemplated nucleotides to the ends before the break is joined.[31][32] This process couples "variable" (V),
"diversity" (D), and "joining" (J) regions, which when assembled together create the variable region of a B-
cell or T-cell receptor gene. Unlike typical cellular NHEJ, in which accurate repair is the most favorable
outcome (https://ghr.nlm.nih.gov/gene/ATM), error-prone repair in V(D)J recombination is beneficial in that it
maximizes diversity in the coding sequence of these genes. Patients with mutations in NHEJ genes are unable
to produce functional B cells and T cells and suffer from severe combined immunodeficiency (SCID).

At telomeres
Telomeres are normally protected by a "cap" that prevents them from being recognized as double-strand
breaks. Loss of capping proteins causes telomere shortening and inappropriate joining by NHEJ, producing
dicentric chromosomes which are then pulled apart during mitosis. Paradoxically, some NHEJ proteins are
involved in telomere capping. For example, Ku localizes to telomeres and its deletion leads to shortened
telomeres.[33] Ku is also required for subtelomeric silencing, the process by which genes located near
telomeres are turned off.

Consequences of dysfunction
Several human syndromes are associated with dysfunctional NHEJ.[34] Hypomorphic mutations in LIG4 and
XLF cause LIG4 syndrome and XLF-SCID, respectively. These syndromes share many features including
cellular radiosensitivity, microcephaly and severe combined immunodeficiency (SCID) due to defective V(D)J
recombination. Loss-of-function mutations in Artemis also cause SCID, but these patients do not show the
neurological defects associated with LIG4 or XLF mutations. The difference in severity may be explained by
the roles of the mutated proteins. Artemis is a nuclease and is thought to be required only for repair of DSBs
with damaged ends, whereas DNA Ligase IV and XLF are required for all NHEJ events. Mutations in genes
that participate in non-homologous end joining lead to ataxia-telangiectasia (ATM gene) (https://ghr.nlm.nih.go
v/gene/ATM), Fanconi anemia (multiple genes), as well as hereditary breast and ovarian cancers (BRCA1
gene).

Many NHEJ genes have been knocked out in mice. Deletion of XRCC4 or LIG4 causes embryonic lethality
in mice, indicating that NHEJ is essential for viability in mammals. In contrast, mice lacking Ku or DNA-PKcs
are viable, probably because low levels of end joining can still occur in the absence of these components.[35]
All NHEJ mutant mice show a SCID phenotype, sensitivity to ionizing radiation, and neuronal apoptosis.

Aging
A system was developed for measuring NHEJ efficiency in the mouse.[36] NHEJ efficiency could be
compared across tissues of the same mouse and in mice of different age. Efficiency was higher in the skin,
lung and kidney fibroblasts, and lower in heart fibroblasts and brain astrocytes. Furthermore, NHEJ efficiency
declined with age. The decline was 1.8 to 3.8-fold, depending on the tissue, in the 5 month old compared to
the 24-month old mice. Reduced capability for NHEJ can lead to an increase in the number of unrepaired or
faultily repaired DNA double-strand breaks that may then contribute to aging.[37] (Also see DNA damage
theory of aging.) An analysis of the level of NHEJ protein Ku80 in human, cow, and mouse indicated that
Ku80 levels vary dramatically between species, and that these levels are strongly correlated with species
longevity.[38]

List of proteins involved in NHEJ in human cells

Ku70/80
DNA-PKcs
DNA Ligase IV
XRCC4
 XLF
Artemis
DNA polymerase mu
DNA polymerase lambda
PNKP
Aprataxin
APLF
BRCA1
BRCA2
CYREN

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