PCNA
Encyclopedia
Proliferating Cell Nuclear Antigen, commonly known as PCNA, is a protein
that acts as a processivity
factor for DNA polymerase δ
in eukaryotic cells
. It achieves this processivity
by encircling the DNA, thus creating a topological link to the genome
. It is an example of a DNA clamp
.
that is expressed in the nuclei
of cells during the DNA synthesis phase
of the cell cycle
. Part of the protein was sequenced and that sequence was used to allow isolation of a cDNA clone. PCNA helps hold DNA polymerase
delta (Pol δ) to DNA. PCNA is clamped to DNA
through the action of replication factor C
(RFC), which is a heteropentameric member of the AAA+ class of ATPases. Expression of PCNA is under the control of E2F
transcription factor
-containing complexes.
, PCNA is important for both DNA synthesis and DNA repair.
PCNA is also involved in the DNA damage tolerance pathway known as post-replication repair (PRR). In PRR, there are two sub-pathways:
(1) a translesion pathway, which is carried out by specialised DNA polymerases that are able to incorporate damaged DNA bases into their active sites (unlike the normal replicative polymerase, which stall), and hence bypass the damage, and
(2) a proposed "template switch" pathway that is thought to involve damage bypass by recruitment of the homologous recombination machinery.
PCNA is pivotal to the activation of these pathways and the choice as to which pathway is utilised by the cell. PCNA becomes post-translationally modified by ubiquitin
. Mono-ubiquitin of lysine number 164 on PCNA activates the translesion synthesis pathway. Extension of this mono-ubiquitin by a non-canonical lysine-63-linked poly-ubiquitin chain on PCNA is thought to activate the template switch pathway. Furthermore, sumoylation (by small ubiquitin-like modifier, SUMO) of PCNA lysine-164 (and to a lesser extent, lysine-127) inhibits the template switch pathway. This antagonistic effect occurs because sumoylated PCNA recruits a DNA helicase called Srs2, which has a role in disrupting Rad51 nucleoprotein filaments fundamental for initiation of homologous recombination.
Flap endonuclease
DNA ligase
Topoisomerase
Replication licensing factor E3 ubiquitin ligases E2 SUMO
-conjugating enzyme Helicase
s, ATPases Mismatch repair enzymes Base excision repair
enzymes Nucleotide excision repair
enzyme Poly ADP ribose polymerase
Histone
chaperone Chromatin remodeling factor
Histone acetyltransferase
Histone deacetyltransferase DNA methyltransferase
Sister-chromatid cohesion factors
Protein kinases Cell-cycle regulators Apoptotic factors
for details see
with Ku70, MSH3
, Werner syndrome ATP-dependent helicase, RFC2
, RFC3
, RFC1
, RFC4
, RFC5
, GADD45G
, CDC25C
, MUTYH
, Flap structure-specific endonuclease 1
, Cyclin O
, CHTF18
, Y box binding protein 1
, Cyclin D1
, Annexin A2
, MSH6
, DNMT1
, HDAC1
, KCTD13
, XRCC1
, Cyclin-dependent kinase 4
, Ku80, HUS1
, GADD45A
, POLD2
, ING1
, POLH
, KIAA0101
, POLDIP2
, EP300
, MCL1
, POLD3
, Cyclin-dependent kinase inhibitor 1C
, POLL
, Ubiquitin C
and P21
.
against proliferating cell nuclear antigen (PCNA) or monoclonal antibody termed Ki-67
can be used for grading of different neoplasms, e.g. astrocytoma
. They can be of diagnostic
and prognostic
value.
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...
that acts as a processivity
Processivity
In molecular biology, processivity is a measure of the average number of nucleotides added by a DNA polymerase enzyme per association/disassociation with the template. DNA polymerases associated with DNA replication tend to be highly processive, while those associated with DNA repair tend to have...
factor for DNA polymerase δ
DNA polymerase delta
DNA polymerase delta is an enzyme complex found in eukaryotes that is involved in DNA replication and repair, and it consists of the proliferating cell nuclear antigen , the multisubunit replication factor C, and the 4 subunit polymerase complex: POLD1, POLD2, POLD3, and POLD4....
in eukaryotic cells
Cell (biology)
The cell is the basic structural and functional unit of all known living organisms. It is the smallest unit of life that is classified as a living thing, and is often called the building block of life. The Alberts text discusses how the "cellular building blocks" move to shape developing embryos....
. It achieves this processivity
Processivity
In molecular biology, processivity is a measure of the average number of nucleotides added by a DNA polymerase enzyme per association/disassociation with the template. DNA polymerases associated with DNA replication tend to be highly processive, while those associated with DNA repair tend to have...
by encircling the DNA, thus creating a topological link to the genome
Genome
In modern molecular biology and genetics, the genome is the entirety of an organism's hereditary information. It is encoded either in DNA or, for many types of virus, in RNA. The genome includes both the genes and the non-coding sequences of the DNA/RNA....
. It is an example of a DNA clamp
DNA clamp
A DNA clamp, also known as a sliding clamp, is a protein fold that serves as a processivity-promoting factor in DNA replication. As a critical component of the DNA polymerase III holoenzyme, the clamp protein binds DNA polymerase and prevents this enzyme from dissociating from the template DNA strand...
.
Expression in the nucleus during DNA synthesis
PCNA was originally identified as an antigenAntigen
An antigen is a foreign molecule that, when introduced into the body, triggers the production of an antibody by the immune system. The immune system will then kill or neutralize the antigen that is recognized as a foreign and potentially harmful invader. These invaders can be molecules such as...
that is expressed in the nuclei
Cell nucleus
In cell biology, the nucleus is a membrane-enclosed organelle found in eukaryotic cells. It contains most of the cell's genetic material, organized as multiple long linear DNA molecules in complex with a large variety of proteins, such as histones, to form chromosomes. The genes within these...
of cells during the DNA synthesis phase
S phase
S-phase is the part of the cell cycle in which DNA is replicated, occurring between G1 phase and G2 phase. Precise and accurate DNA replication is necessary to prevent genetic abnormalities which often lead to cell death or disease. Due to the importance, the regulatory pathways that govern this...
of the cell cycle
Cell cycle
The cell cycle, or cell-division cycle, is the series of events that takes place in a cell leading to its division and duplication . In cells without a nucleus , the cell cycle occurs via a process termed binary fission...
. Part of the protein was sequenced and that sequence was used to allow isolation of a cDNA clone. PCNA helps hold DNA polymerase
DNA polymerase
A DNA polymerase is an enzyme that helps catalyze in the polymerization of deoxyribonucleotides into a DNA strand. DNA polymerases are best known for their feedback role in DNA replication, in which the polymerase "reads" an intact DNA strand as a template and uses it to synthesize the new strand....
delta (Pol δ) to DNA. PCNA is clamped to DNA
DNA
Deoxyribonucleic acid is a nucleic acid that contains the genetic instructions used in the development and functioning of all known living organisms . The DNA segments that carry this genetic information are called genes, but other DNA sequences have structural purposes, or are involved in...
through the action of replication factor C
Replication factor C
The replication factor C, or RFC, is a five-subunit protein complex that is required for DNA replication.The subunits of this heteropentamer are named Rfc1, Rfc2, Rfc3, Rfc4, and Rfc5 . RFC is used in eukaryotic replication as a clamp loader, similar to the γ Complex in E. coli. Its role as clamp...
(RFC), which is a heteropentameric member of the AAA+ class of ATPases. Expression of PCNA is under the control of E2F
E2F
E2F is a group of genes that codifies a family of transcription factors in higher eukaryotes. Three of them are activators: E2F1, 2 and E2F3a. Six others act as suppressors: E2F3b, E2F4-8. All of them are involved in the cell cycle regulation and synthesis of DNA in mammalian cells...
transcription factor
Transcription factor
In molecular biology and genetics, a transcription factor is a protein that binds to specific DNA sequences, thereby controlling the flow of genetic information from DNA to mRNA...
-containing complexes.
Role in DNA repair
Since DNA polymerase delta is involved in resynthesis of excised damaged DNA strands during DNA repairDNA repair
DNA repair refers to 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 UV light and radiation can cause DNA damage, resulting in as many as 1...
, PCNA is important for both DNA synthesis and DNA repair.
PCNA is also involved in the DNA damage tolerance pathway known as post-replication repair (PRR). In PRR, there are two sub-pathways:
(1) a translesion pathway, which is carried out by specialised DNA polymerases that are able to incorporate damaged DNA bases into their active sites (unlike the normal replicative polymerase, which stall), and hence bypass the damage, and
(2) a proposed "template switch" pathway that is thought to involve damage bypass by recruitment of the homologous recombination machinery.
PCNA is pivotal to the activation of these pathways and the choice as to which pathway is utilised by the cell. PCNA becomes post-translationally modified by ubiquitin
Ubiquitin
Ubiquitin is a small regulatory protein that has been found in almost all tissues of eukaryotic organisms. Among other functions, it directs protein recycling.Ubiquitin can be attached to proteins and label them for destruction...
. Mono-ubiquitin of lysine number 164 on PCNA activates the translesion synthesis pathway. Extension of this mono-ubiquitin by a non-canonical lysine-63-linked poly-ubiquitin chain on PCNA is thought to activate the template switch pathway. Furthermore, sumoylation (by small ubiquitin-like modifier, SUMO) of PCNA lysine-164 (and to a lesser extent, lysine-127) inhibits the template switch pathway. This antagonistic effect occurs because sumoylated PCNA recruits a DNA helicase called Srs2, which has a role in disrupting Rad51 nucleoprotein filaments fundamental for initiation of homologous recombination.
PCNA-binding proteins
NKp44 Receptor, DNA polymerases Clamp loaderReplication factor C
The replication factor C, or RFC, is a five-subunit protein complex that is required for DNA replication.The subunits of this heteropentamer are named Rfc1, Rfc2, Rfc3, Rfc4, and Rfc5 . RFC is used in eukaryotic replication as a clamp loader, similar to the γ Complex in E. coli. Its role as clamp...
Flap endonuclease
Flap endonuclease
Flap endonucleases are a class of nucleolytic enzymes that act as both 5'-3' exonucleases and structure specific endonucleases on specialised DNA structures that occur during the biological processes of DNA replication, DNA repair and DNA recombination...
DNA ligase
DNA ligase
In molecular biology, DNA ligase is a specific type of enzyme, a ligase, that repairs single-stranded discontinuities in double stranded DNA molecules, in simple words strands that have double-strand break . Purified DNA ligase is used in gene cloning to join DNA molecules together...
Topoisomerase
Topoisomerase
Topoisomerases are enzymes that regulate the overwinding or underwinding of DNA. The winding problem of DNA arises due to the intertwined nature of its double helical structure. For example, during DNA replication, DNA becomes overwound ahead of a replication fork...
Replication licensing factor E3 ubiquitin ligases E2 SUMO
SUMO protein
Small Ubiquitin-like Modifier or SUMO proteins are a family of small proteins that are covalently attached to and detached from other proteins in cells to modify their function...
-conjugating enzyme Helicase
Helicase
Helicases are a class of enzymes vital to all living organisms. They are motor proteins that move directionally along a nucleic acid phosphodiester backbone, separating two annealed nucleic acid strands using energy derived from ATP hydrolysis.-Function:Many cellular processes Helicases are a...
s, ATPases Mismatch repair enzymes Base excision repair
Base excision repair
In biochemistry and genetics, base excision repair is a cellular mechanism that repairs damaged DNA throughout the cell cycle. It is responsible primarily for removing small, non-helix-distorting base lesions from the genome. The related nucleotide excision repair pathway repairs bulky...
enzymes Nucleotide excision repair
Nucleotide excision repair
Nucleotide excision repair is a DNA repair mechanism. DNA constantly requires repair due to damage that can occur to bases from a vast variety of sources including chemicals, radiation and other mutagens...
enzyme Poly ADP ribose polymerase
Poly ADP ribose polymerase
Poly polymerase is a family of proteins involved in a number of cellular processes involving mainly DNA repair and programmed cell death.-Members of PARP family:The PARP family comprises 17 members...
Histone
Histone
In biology, histones are highly alkaline proteins found in eukaryotic cell nuclei that package and order the DNA into structural units called nucleosomes. They are the chief protein components of chromatin, acting as spools around which DNA winds, and play a role in gene regulation...
chaperone Chromatin remodeling factor
Chromatin remodeling
Chromatin remodeling is the enzyme-assisted movement of nucleosomes on DNA.This is performed by chromatin remodeling complexes like SWI/SNF , RSC and Imitation SWI complexes ....
Histone acetyltransferase
Histone acetyltransferase
Histone acetyltransferases are enzymes that acetylate conserved lysine amino acids on histone proteins by transferring an acetyl group from acetyl CoA to form ε-N-acetyl lysine....
Histone deacetyltransferase DNA methyltransferase
DNA methyltransferase
In biochemistry, the DNA methyltransferase family of enzymescatalyze the transfer of a methyl group to DNA. DNA methylation serves a wide variety of biological functions...
Sister-chromatid cohesion factors
Cohesin
Cohesin is a protein complex that regulates the separation of sister chromatids during cell division, either mitosis or meiosis.- Structure :...
Protein kinases Cell-cycle regulators Apoptotic factors
for details see
Interactions
PCNA 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 Ku70, MSH3
MSH3
DNA mismatch repair protein Msh3 is a protein that in humans is encoded by the MSH3 gene.-Interactions:MSH3 has been shown to interact with MSH2, PCNA and BRCA1.-Further reading:...
, Werner syndrome ATP-dependent helicase, RFC2
RFC2
Replication factor C subunit 2 is a protein that in humans is encoded by the RFC2 gene.-Interactions:RFC2 has been shown to interact with BRD4, CHTF18, PCNA, RFC4 and RFC5.-Further reading:...
, RFC3
RFC3
Replication factor C subunit 3 is a protein that in humans is encoded by the RFC3 gene.-Interactions:RFC3 has been shown to interact with BRD4, CHTF18, RFC1, PCNA and RFC4.-Further reading:...
, RFC1
RFC1
Replication factor C subunit 1 is a protein that in humans is encoded by the RFC1 gene.-Interactions:RFC1 has been shown to interact with BRD4, HDAC1, RFC3, RELA and PCNA.-Further reading:...
, RFC4
RFC4
Replication factor C subunit 4 is a protein that in humans is encoded by the RFC4 gene.-Interactions:RFC4 has been shown to interact with BRD4, RFC2, RFC3, CHTF18, PCNA and RFC5.-Further reading:...
, RFC5
RFC5
Replication factor C subunit 5 is a protein that in humans is encoded by the RFC5 gene.-Interactions:RFC5 has been shown to interact with BRD4, RFC2, PCNA, RFC4 and CHTF18.-Further reading:...
, GADD45G
GADD45G
Growth arrest and DNA-damage-inducible protein GADD45 gamma is a protein that in humans is encoded by the GADD45G gene.-Interactions:GADD45G has been shown to interact with MAP3K4, PCNA, GADD45GIP1 and P21.-Further reading:...
, CDC25C
CDC25C
M-phase inducer phosphatase 3 is an enzyme that in humans is encoded by the CDC25C gene.-Interactions:CDC25C has been shown to interact with MAPK14, CHEK1, PCNA, PIN1, PLK3 and NEDD4.-Further reading:...
, MUTYH
MUTYH
MUTYH is a human gene encoding a DNA glycosylase, MUTYH glycosylase, involved in oxidative DNA damage repair. The enzyme excises adenine bases from the DNA backbone at sites where adenine is inappropriately paired with guanine, cytosine, or 8-oxo-7,8-dihydroguanine, a major oxidatively damaged DNA...
, Flap structure-specific endonuclease 1
Flap structure-specific endonuclease 1
Flap endonuclease 1 is an enzyme that in humans is encoded by the FEN1 gene.-Interactions:Flap structure-specific endonuclease 1 has been shown to interact with Cyclin-dependent kinase 2, EP300, Werner syndrome ATP-dependent helicase, Heterogeneous nuclear ribonucleoprotein A1, Cyclin A2, PCNA,...
, Cyclin O
Cyclin O
Cyclin-O is a protein that in humans is encoded by the CCNO gene.-Interactions:Cyclin O has been shown to interact with RPA2 and PCNA.-Further reading:...
, CHTF18
CHTF18
Chromosome transmission fidelity protein 18 homolog is a protein that in humans is encoded by the CHTF18 gene.-Interactions:CHTF18 has been shown to interact with DCC1, RFC2, RFC3, PCNA, RFC4 and RFC5.-Further reading:...
, Y box binding protein 1
Y box binding protein 1
Y box binding protein 1, officially known as YBX1, but commonly referred to as "YB-1" by researchers, is a human protein. Current research is examining its involvement in cancer, and particularly in the metastasis of cancerous cells or prevention thereof....
, Cyclin D1
Cyclin D1
G1/S-specific cyclin-D1 is a protein that in humans is encoded by the CCND1 gene.Immunohistochemical staining of cyclin D1 antibodies is used to diagnose mantle cell lymphoma.-Interactions:...
, Annexin A2
Annexin A2
Annexin A2 also known as annexin II is a protein that in humans is encoded by the ANXA2 gene.Annexin 2 is involved in diverse cellular processes such as cell motility , linkage of membrane-associated protein complexes to the actin cytoskeleton, endocytosis, fibrinolysis, ion channel formation, and...
, MSH6
MSH6
MSH6 is a gene commonly associated with hereditary nonpolyposis colorectal cancer.-Function:MSH6 contributes to ADP and ATP binding. It also contributes to ATPase activity...
, DNMT1
DNMT1
DNA -methyltransferase 1 is an enzyme that in humans is encoded by the DNMT1 gene.-Interactions:DNMT1 has been shown to interact with Histone deacetylase 2, DMAP1, PCNA, Retinoblastoma protein, DNMT3A and DNMT3B.-Further reading:...
, HDAC1
HDAC1
Histone deacetylase 1 is an enzyme that in humans is encoded by the HDAC1 gene.-Interactions:HDAC1 has been shown to interact with RAD9A, DNMT3L, MTA1, FKBP3, CDC20, CDH1, Host cell factor C1, BUB3, Nuclear receptor co-repressor 2, IKZF1, Prohibitin, EVI1, DDX5, DNMT3A, Mothers against...
, KCTD13
KCTD13
BTB/POZ domain-containing protein KCTD13 is a protein that in humans is encoded by the KCTD13 gene.-Further reading:...
, XRCC1
XRCC1
XRCC1 is a DNA repair protein.It complexes with DNA ligase III.-Interactions:XRCC1 has been shown to interact with PARP2, DNA polymerase beta, Aprataxin, Oxoguanine glycosylase, PCNA, APEX1, PNKP and PARP1.-Further reading:-External links:...
, Cyclin-dependent kinase 4
Cyclin-dependent kinase 4
Cyclin-dependent kinase 4 is part of the cyclin-dependent kinase family.It is regulated by Cyclin D.-Interactions:Cyclin-dependent kinase 4 has been shown to interact with SERTAD1, CDC37, CEBPA, PCNA, Cyclin D3, Cyclin D1, CDKN2C, MyoD, P16, CDKN2B, Drebrin-like and CDKN1B.-External links:...
, Ku80, HUS1
HUS1
Checkpoint protein HUS1 is a protein that in humans is encoded by the HUS1 gene.-Interactions:HUS1 has been shown to interact with RAD9A, RAD17, HDAC1, RAD1 homolog and PCNA.-Further reading:...
, GADD45A
GADD45A
Growth arrest and DNA-damage-inducible protein GADD45 alpha is a protein that in humans is encoded by the GADD45A gene.-Interactions:GADD45A has been shown to interact with, MAP3K4, Cdk1, Cyclin B1, PCNA, GADD45GIP1 and P21. Gadd45a has been recently shown that interacts with Aurora A...
, POLD2
POLD2
DNA polymerase delta subunit 2 is an enzyme that in humans is encoded by the POLD2 gene. It is a component of the DNA polymerase delta complex.-Further reading:...
, ING1
ING1
Inhibitor of growth protein 1 is a protein that in humans is encoded by the ING1 gene.-Location on Chromosome 13:ING1 is located near the following genes on Chromosome 13*CARKD Carbohydrate Kinase Domain-Containing Protein...
, POLH
POLH
Polymerase , eta, also known as POLH, is a protein which in humans is encoded by the POLH gene.-Function:This gene encodes a member of the Y family of specialized DNA polymerases. It copies undamaged DNA with a lower fidelity than other DNA-directed polymerases...
, KIAA0101
KIAA0101
PCNA-associated factor is a protein that in humans is encoded by the KIAA0101 gene.-Further reading:...
, POLDIP2
POLDIP2
Polymerase delta-interacting protein 2 is an enzyme that in humans is encoded by the POLDIP2 gene.-Further reading:...
, EP300
EP300
E1A binding protein p300 also known as EP300 or p300 is a protein that, in humans, is encoded by the EP300 gene. This protein regulates the activity of many genes in tissues throughout the body...
, MCL1
MCL1
Induced myeloid leukemia cell differentiation protein Mcl-1 is a protein that in humans is encoded by the MCL1 gene.- Function :The protein encoded by this gene belongs to the Bcl-2 family. Alternative splicing occurs at this locus and two transcript variants encoding distinct isoforms have been...
, POLD3
POLD3
DNA polymerase delta subunit 3 is an enzyme that in humans is encoded by the POLD3 gene. It is a component of the DNA polymerase delta complex.-Further reading:...
, Cyclin-dependent kinase inhibitor 1C
Cyclin-dependent kinase inhibitor 1C
Cyclin-dependent kinase inhibitor 1C , also known as CDKN1C, is protein which in humans is encoded by the CDKN1C imprinted gene.- Function :...
, POLL
POLL
DNA polymerase lambda, also known as POLL, is a protein that, in humans, is encoded by the POLLA gene.- Function :Pol λ is a member of the X family of DNA polymerases. It is thought to resynthesize missing nucleotides during non-homologous end joining, a pathway of DNA double-strand break repair...
, Ubiquitin C
Ubiquitin C
Ubiquitin is a protein that in humans is encoded by the UBC gene.-Interactions:Ubiquitin C has been shown to interact with SCNN1A, SCNN1G, Parkin , P70-S6 Kinase 1, TRAF6, HDAC3, SFPQ, S100A10, Mothers against decapentaplegic homolog 3, NOTCH1, HIF1A, Epidermal growth factor receptor, E2F1,...
and P21
P21
p21 / WAF1 also known as cyclin-dependent kinase inhibitor 1 or CDK-interacting protein 1 is a protein that in humans is encoded by the CDKN1A gene located on chromosome 6 .- Function :...
.
Uses
AntibodiesAntibody
An antibody, also known as an immunoglobulin, is a large Y-shaped protein used by the immune system to identify and neutralize foreign objects such as bacteria and viruses. The antibody recognizes a unique part of the foreign target, termed an antigen...
against proliferating cell nuclear antigen (PCNA) or monoclonal antibody termed Ki-67
Ki-67 (Biology)
Antigen KI-67 also known as Ki-67 or MKI67 is a protein that in humans is encoded by the MKI67 gene .- Function :...
can be used for grading of different neoplasms, e.g. astrocytoma
Astrocytoma
Astrocytomas are a type of neoplasm of the brain. They originate in a particular kind of glial-cells, star-shaped brain cells in the cerebrum called astrocytes. This type of tumor does not usually spread outside the brain and spinal cord and it does not usually affect other organs...
. They can be of diagnostic
Diagnosis
Diagnosis is the identification of the nature and cause of anything. Diagnosis is used in many different disciplines with variations in the use of logics, analytics, and experience to determine the cause and effect relationships...
and prognostic
Prognosis
Prognosis is a medical term to describe the likely outcome of an illness.When applied to large statistical populations, prognostic estimates can be very accurate: for example the statement "45% of patients with severe septic shock will die within 28 days" can be made with some confidence, because...
value.
See also
- TranscriptionTranscription (genetics)Transcription is the process of creating a complementary RNA copy of a sequence of DNA. Both RNA and DNA are nucleic acids, which use base pairs of nucleotides as a complementary language that can be converted back and forth from DNA to RNA by the action of the correct enzymes...
- Ki-67Ki-67 (Biology)Antigen KI-67 also known as Ki-67 or MKI67 is a protein that in humans is encoded by the MKI67 gene .- Function :...
- cellular marker for proliferation