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.[5]
DNA-PKcs belongs to the
phosphatidylinositol 3-kinase-related
kinase protein family. The DNA-
Pkcs protein is a serine/threonine
protein kinase comprising a single
polypeptide chain of 4,128 amino
acids.[6][7]
Contents
PRKDC
Identifiers
Aliases PRKDC (https://www.genenames.org/data/gene-symbol-r
eport/#!/hgnc_id/9413), DNA-PKcs, DNAPK, DNPK1,
HYRC, HYRC1, XRCC7, p350, IMD26, protein kinase,
DNA-activated, catalytic polypeptide, DNA-PKC, protein
kinase, DNA-activated, catalytic subunit, DNAPKc
External OMIM: 600899 (https://omim.org/entry/600899) MGI:
IDs 104779 (http://www.informatics.jax.org/marker/MGI:1047
79) HomoloGene: 5037 (https://www.ncbi.nlm.nih.gov/ent
rez/query.fcgi?cmd=Retrieve&db=homologene&dopt=Ho
moloGene&list_uids=5037) GeneCards: PRKDC (https://
www.genecards.org/cgi-bin/carddisp.pl?gene=PRKDC)

Function Gene location (Human)

Cancer
Aging
Interactions
See also
References
Chr. Chromosome 8 (human)[1]

Function
DNA-PKcs is the catalytic subunit of Band 8q11.21 Start 47,773,111 bp[1]
a nuclear DNA-dependent
End 47,960,178 bp[1]
serine/threonine protein kinase called
DNA-PK. The second component is Gene location (Mouse)
the autoimmune antigen Ku. On its
own, DNA-PKcs is inactive and
relies on Ku to direct it to DNA ends
and trigger its kinase activity.[8]
DNA-PKcs is required for the non-
homologous end joining (NHEJ)
pathway of DNA repair, which
Chr. Chromosome 16 (mouse)[2]
rejoins double-strand breaks. It is
also required for V(D)J
recombination, a process that utilizes
NHEJ to promote immune system
diversity. DNA-PKcs knockout mice Band 16 10.09 cM|16 A2 Start 15,637,866 bp[2]
End 15,842,235 bp[2]
have severe combined
immunodeficiency due to their V(D)J
recombination defect.
Many proteins have been identified
as substrates for the kinase activity of
DNA-PK. Autophosphorylation of
DNA-PKcs appears to play a key
role in NHEJ and is thought to
induce a conformational change that
allows end processing enzymes to
access the ends of the double-strand
break.[9] DNA-PK also cooperates
with ATR and ATM to
phosphorylate proteins involved in
the DNA damage checkpoint.
Cancer
DNA damage appears to be the
primary underlying cause of
cancer,[10] and deficiencies in DNA
repair genes likely underlie many
forms of cancer.[11][12] If DNA
repair is deficient, DNA damage
tends to accumulate. Such excess
DNA damage may increase
mutations due to error-prone
translesion synthesis. Excess DNA
damage may also increase epigenetic
alterations due to errors during DNA
repair.[13][14] Such mutations and
epigenetic alterations may give rise to
cancer.
PRKDC (DNA-PKcs) mutations
were found in 3 out of 10 of
endometriosis-associated ovarian
cancers, as well as in the field defects
from which they arose.[15] They
were also found in 10% of breast and
pancreatic cancers.[16]
Reductions in expression of DNA
repair genes (usually caused by
epigenetic alterations) are very
common in cancers, and are
ordinarily even more frequent than
mutational defects in DNA repair
genes in cancers. DNA-PKcs
expression was reduced by 23% to
57% in six cancers as indicated in the
Gene ontology
Molecular • transferase activity (http://amigo.geneontology.org/a
function migo/term/GO:0016740)
• nucleotide binding (http://amigo.geneontology.org/a
migo/term/GO:0000166)
• DNA binding (http://amigo.geneontology.org/amigo/t
erm/GO:0003677)
• DNA-dependent protein kinase activity (http://amigo.
geneontology.org/amigo/term/GO:0004677)
• transcription factor binding (http://amigo.geneontolo
gy.org/amigo/term/GO:0008134)
• kinase activity (http://amigo.geneontology.org/amigo/
term/GO:0016301)
• protein serine/threonine kinase activity (http://amigo.
geneontology.org/amigo/term/GO:0004674)
• GO:0001948 protein binding (http://amigo.geneontol
ogy.org/amigo/term/GO:0005515,)
• enzyme binding (http://amigo.geneontology.org/amig
o/term/GO:0019899)
• ATP binding (http://amigo.geneontology.org/amigo/te
rm/GO:0005524)
• RNA binding (http://amigo.geneontology.org/amigo/t
erm/GO:0003723)
• double-stranded DNA binding (http://amigo.geneont
ology.org/amigo/term/GO:0003690)
• protein kinase activity (http://amigo.geneontology.or
g/amigo/term/GO:0004672)
• protein domain specific binding (http://amigo.geneon
tology.org/amigo/term/GO:0019904)
Cellular • cytosol (http://amigo.geneontology.org/amigo/term/G
component O:0005829)
• membrane (http://amigo.geneontology.org/amigo/ter
m/GO:0016020)
• transcription factor complex (http://amigo.geneontolo
gy.org/amigo/term/GO:0005667)
• nucleoplasm (http://amigo.geneontology.org/amigo/t
erm/GO:0005654)
• DNA-dependent protein kinase-DNA ligase 4
complex (http://amigo.geneontology.org/amigo/term/G
O:0005958)
• nonhomologous end joining complex (http://amigo.g
eneontology.org/amigo/term/GO:0070419)
• nuclear chromosome, telomeric region (http://amigo.
geneontology.org/amigo/term/GO:0000784)
• extracellular matrix (http://amigo.geneontology.org/a
migo/term/GO:0031012)
table. • cell nucleus (http://amigo.geneontology.org/amigo/te
rm/GO:0005634)
• protein-DNA complex (http://amigo.geneontology.or
g/amigo/term/GO:0032993)
• nucleolus (http://amigo.geneontology.org/amigo/ter
m/GO:0005730)
• macromolecular complex (http://amigo.geneontolog
y.org/amigo/term/GO:0032991)
Biological • somitogenesis (http://amigo.geneontology.org/amig
process o/term/GO:0001756)
• negative regulation of protein phosphorylation (htt
p://amigo.geneontology.org/amigo/term/GO:0001933)
• response to ionizing radiation (http://amigo.geneonto
logy.org/amigo/term/GO:0010212)
• negative regulation of response to gamma radiation
(http://amigo.geneontology.org/amigo/term/GO:20012
29)
• positive regulation of immune system process (http://
amigo.geneontology.org/amigo/term/GO:0002684)
• DNA recombination (http://amigo.geneontology.org/a
migo/term/GO:0006310)
• positive regulation of developmental growth (http://a
migo.geneontology.org/amigo/term/GO:0048639)
• T cell differentiation in thymus (http://amigo.geneont
ology.org/amigo/term/GO:0033077)
• signal transduction involved in mitotic G1 DNA
damage checkpoint (http://amigo.geneontology.org/a
migo/term/GO:0072431)
• telomere capping (http://amigo.geneontology.org/am
igo/term/GO:0016233)
• phosphorylation (http://amigo.geneontology.org/amig
o/term/GO:0016310)
• rhythmic process (http://amigo.geneontology.org/ami
go/term/GO:0048511)
• thymus development (http://amigo.geneontology.org/
amigo/term/GO:0048538)
• positive regulation of fibroblast proliferation (http://a
migo.geneontology.org/amigo/term/GO:0048146)
• lymphocyte differentiation (http://amigo.geneontolog
y.org/amigo/term/GO:0030098)
• T cell receptor V(D)J recombination (http://amigo.ge
neontology.org/amigo/term/GO:0033153)
• negative regulation of apoptotic process (http://amig
o.geneontology.org/amigo/term/GO:0043066)
• double-strand break repair via alternative
nonhomologous end joining (http://amigo.geneontolog
y.org/amigo/term/GO:0097681)
• spleen development (http://amigo.geneontology.org/
amigo/term/GO:0048536)
• negative regulation of immunoglobulin production (ht
tp://amigo.geneontology.org/amigo/term/GO:0002638)
• response to activity (http://amigo.geneontology.org/a
migo/term/GO:0014823)
• regulation of smooth muscle cell proliferation (http://
amigo.geneontology.org/amigo/term/GO:0048660)
• cellular response to DNA damage stimulus (http://am
igo.geneontology.org/amigo/term/GO:0006974)
• heart development (http://amigo.geneontology.org/a
migo/term/GO:0007507)
• pro-B cell differentiation (http://amigo.geneontology.
org/amigo/term/GO:0002328)
• brain development (http://amigo.geneontology.org/a
migo/term/GO:0007420)
• B cell lineage commitment (http://amigo.geneontolog
y.org/amigo/term/GO:0002326)
• cellular protein modification process (http://amigo.ge
neontology.org/amigo/term/GO:0006464)
• peptidyl-serine phosphorylation (http://amigo.geneon
tology.org/amigo/term/GO:0018105)
• protein destabilization (http://amigo.geneontology.or
g/amigo/term/GO:0031648)
• regulation of circadian rhythm (http://amigo.geneont
ology.org/amigo/term/GO:0042752)
• intrinsic apoptotic signaling pathway in response to
DNA damage (http://amigo.geneontology.org/amigo/te
rm/GO:0008630)
• V(D)J recombination (http://amigo.geneontology.org/
amigo/term/GO:0033151)
• cellular response to insulin stimulus (http://amigo.ge
neontology.org/amigo/term/GO:0032869)
• positive regulation of apoptotic process (http://amig
o.geneontology.org/amigo/term/GO:0043065)
• ectopic germ cell programmed cell death (http://amig
o.geneontology.org/amigo/term/GO:0035234)
• immunoglobulin V(D)J recombination (http://amigo.g
eneontology.org/amigo/term/GO:0033152)
• cellular proliferation (http://amigo.geneontology.org/a
migo/term/GO:0008283)
• double-strand break repair via nonhomologous end
joining (http://amigo.geneontology.org/amigo/term/G
O:0006303)
• telomere maintenance (http://amigo.geneontology.or
 g/amigo/term/GO:0000723)
• response to gamma radiation (http://amigo.geneonto
logy.org/amigo/term/GO:0010332)
• positive regulation of type I interferon production (htt
p://amigo.geneontology.org/amigo/term/GO:0032481)
• T cell lineage commitment (http://amigo.geneontolog
y.org/amigo/term/GO:0002360)
• positive regulation of transcription from RNA
polymerase II promoter (http://amigo.geneontology.or
g/amigo/term/GO:0045944)
• negative regulation of cellular senescence (http://ami
go.geneontology.org/amigo/term/GO:2000773)
• immunoglobulin production (http://amigo.geneontolo
gy.org/amigo/term/GO:0002377)
• double-strand break repair (http://amigo.geneontolo
gy.org/amigo/term/GO:0006302)
• DNA repair (http://amigo.geneontology.org/amigo/ter
m/GO:0006281)
• protein ubiquitination (http://amigo.geneontology.org/
amigo/term/GO:0016567)
• protein phosphorylation (http://amigo.geneontology.o
rg/amigo/term/GO:0006468)
• activation of innate immune response (http://amigo.g
eneontology.org/amigo/term/GO:0002218)
• immune system process (http://amigo.geneontology.
org/amigo/term/GO:0002376)
• innate immune system (http://amigo.geneontology.or
g/amigo/term/GO:0045087)
• regulation of epithelial cell proliferation (http://amigo.
geneontology.org/amigo/term/GO:0050678)
• positive regulation of double-strand break repair via
nonhomologous end joining (http://amigo.geneontolog
y.org/amigo/term/GO:2001034)
Sources:Amigo (http://amigo.geneontology.org/) / QuickGO (https://
www.ebi.ac.uk/QuickGO/)

Orthologs
Species Human Mouse
Entrez
5591 (https://www.ncb 19090 (https://www.ncbi.
i.nlm.nih.gov/entrez/qu nlm.nih.gov/entrez/query.f
ery.fcgi?db=gene&cm cgi?db=gene&cmd=retrie
d=retrieve&dopt=defa ve&dopt=default&list_uid
ult&list_uids=5591&rn s=19090&rn=1)
=1)

Ensembl
 ENSG00000253729 ENSMUSG00000022672
(http://www.ensembl.o (http://www.ensembl.org/
rg/Homo_sapiens/gen Mus_musculus/genevie
eview?gene=ENSG00 w?gene=ENSMUSG000
000253729;db=core) 00022672;db=core)

UniProt
P78527 (https://www.u P97313 (https://www.unip
niprot.org/uniprot/P78 rot.org/uniprot/P97313)
527)

RefSeq
(mRNA) NM_001081640 (http NM_011159 (https://ww
s://www.ncbi.nlm.nih.g w.ncbi.nlm.nih.gov/entre
ov/entrez/viewer.fcgi? z/viewer.fcgi?val=NM_01
val=NM_001081640) 1159)
NM_006904 (https://w
ww.ncbi.nlm.nih.gov/e
ntrez/viewer.fcgi?val=
NM_006904)

RefSeq
(protein) NP_001075109 (http NP_035289 (https://www.
s://www.ncbi.nlm.nih.g ncbi.nlm.nih.gov/entrez/vi
ov/entrez/viewer.fcgi? ewer.fcgi?val=NP_03528
val=NP_001075109) 9)
NP_008835 (https://w
ww.ncbi.nlm.nih.gov/e
ntrez/viewer.fcgi?val=
NP_008835)

Location Chr 8: 47.77 – 47.96 Mb Chr 16: 15.64 – 15.84 Mb (ht

(UCSC) (https://genome.ucsc.edu/
cgi-bin/hgTracks?org=Hu
man&db=hg38&position=c
hr8:47773111-47960178)
PubMed [3]
tps://genome.ucsc.edu/cgi-bi
n/hgTracks?org=Mouse&db=
mm0&position=chr16:156378
66-15842235)
[4]

search
Wikidata

View/Edit Human View/Edit Mouse

 Frequency of reduced expression of DNA-PKcs in sporadic cancers
Cancer Frequency of reduction in cancer Ref.

Breast cancer 57% [17]

Prostate cancer 51% [18]

Cervical carcinoma 32% [19]

Nasopharyngeal carcinoma 30% [20]

Epithelial ovarian cancer 29% [21]

Gastric cancer 23% [22]

It is not clear what causes reduced expression of DNA-PKcs in cancers. MicroRNA-101 targets DNA-PKcs
via binding to the 3'- UTR of DNA-PKcs mRNA and efficiently reduces protein levels of DNA-PKcs.[23] But
miR-101 is more often decreased in cancers, rather than increased.[24][25]

HMGA2 protein could also have an effect on DNA-PKcs. HMGA2 delays the release of DNA-PKcs from
sites of double-strand breaks, interfering with DNA repair by non-homologous end joining and causing
chromosomal aberrations.[26] The let-7a microRNA normally represses the HMGA2 gene.[27][28] In normal
adult tissues, almost no HMGA2 protein is present. In many cancers, let-7 microRNA is repressed. As an
example, in breast cancers the promoter region controlling let-7a-3/let-7b microRNA is frequently repressed by
hypermethylation.[29] Epigenetic reduction or absence of let-7a microRNA allows high expression of the
HMGA2 protein and this would lead to defective expression of DNA-PKcs.

DNA-PKcs can be up-regulated by stressful conditions such as in Helicobacter pylori-associated gastritis.[30]

After ionizing radiation DNA-PKcs was increased in the surviving cells of oral squamous cell carcinoma
tissues.[31]

The ATM protein is important in homologous recombinational repair (HRR) of DNA double strand breaks.
When cancer cells are deficient in ATM the cells are "addicted" to DNA-PKcs, important in the alternative
DNA repair pathway for double-strand breaks, non-homologous end joining (NHEJ).[32] That is, in ATM-
mutant cells, an inhibitor of DNA-PKcs causes high levels of apoptotic cell death. In ATM mutant cells,
additional loss of DNA-PKcs leaves the cells without either major pathway (HRR and NHEJ) for repair of
DNA double-strand breaks.

Elevated DNA-PKcs expression is found in a large fraction (40% to 90%) of some cancers (the remaining
fraction of cancers often has reduced or absent expression of DNA-PKcs). The elevation of DNA-PKcs is
thought to reflect the induction of a compensatory DNA repair capability, due to the genome instability in
these cancers.[33] (As indicated in the article Genome instability, such genome instability may be due to
deficiencies in other DNA repair genes present in the cancers.) Elevated DNA-PKcs is thought to be
"beneficial to the tumor cells",[33] though it would be at the expense of the patient. As indicated in a table
listing 12 types of cancer reported in 20 publications,[33] the fraction of cancers with over-expression of DNA-
PKcs is often associated with an advanced stage of the cancer and shorter survival time for the patient.
However, the table also indicates that for some cancers, the fraction of cancers with reduced or absent DNA-
PKcs is also associated with advanced stage and poor patient survival.

Aging
Non-homologous end joining (NHEJ) is the principal DNA repair process used by mammalian somatic cells to
cope with double-strand breaks that continually occur in the genome. DNA-PKcs is one of the key
components of the NHEJ machinery. DNA-PKcs deficient mice have a shorter lifespan and show an earlier
onset of numerous aging related pathologies than corresponding wild-type littermates.[34][35] These findings
suggest that failure to efficiently repair DNA double-strand breaks results in premature aging, consistent with
the DNA damage theory of aging. (See also Bernstein et al.[36])

Interactions
DNA-PKcs has been shown to interact with:

ATM,[37][38] ILF2,[45]
C1D,[39] and ILF3,[45]
CDC5L,[40] Ku80,[46][47][48]
CHEK1,[37][41] NCOA6,[49]
CHUK,[42] P53,[37][39][41]
CIB1,[43] RPA2,[50] and
DCLRE1C,[44] WRN.[37][51]

See also
Non-homologous end joining
V(D)J recombination
Ku
Protein kinase

References
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