PARP1
Encyclopedia
Poly [ADP-ribose] polymerase 1 (PARP-1) also known as NAD+ ADP-ribosyltransferase 1 or poly[ADP-ribose] synthase 1 is an enzyme
that in humans is encoded by the PARP1 gene
.
PARP1 is involved in:
PARP1 is activated by:
or inhibiting PARP1 activity with small molecules reduces repair of ssDNA breaks. In the absence of PARP1, when these breaks are encountered during DNA replication
, the replication fork
stalls, and double-strand DNA (dsDNA) breaks accumulate. These dsDNA breaks are repaired via homologous recombination
(HR) repair, a potentially error-free repair mechanism. For this reason, cells lacking PARP1 show a hyper-recombinagenic phenotype (e.g., an increased frequency of HR), which has also been observed in vivo
in mice using the pun assay. Thus, if the HR pathway is functioning, PARP1 null mutants (cells without functioning PARP1) do not show an unhealthy phenotype, and in fact, PARP1 knockout mice show no negative phenotype and no increased incidence of tumor formation.
and BRCA2
are at least partially necessary for the HR pathway to function. Therefore, cells that are deficient in BRCA1 or BRCA2 have been shown to be highly sensitive to PARP1 inhibition or knock-down, resulting in cell death by apoptosis
, in stark contrast to cells with at least one good copy of both BRCA1 and BRCA2. Many breast cancers have defects in the BRCA1/BRCA2 HR repair pathway due to mutations in either BRCA1 or BRCA2, or other essential genes in the pathway (the latter termed cancers with "BRCAness"). Tumors with BRCAness are hypothesized to be highly sensitive to PARP1 inhibitors, and it has been demonstrated in mice that these inhibitors can both prevent BRCA1/2-deficient xenografts from becoming tumors and eradicate tumors having previously formed from BRCA1/2-deficient xenografts.
s may prove highly effective therapies for cancers with BRCAness, due to the high sensitivity of the tumors to the inhibitor and the lack of deleterious effects on the remaining healthy cells with functioning BRCA HR pathway. This is in contrast to conventional chemotherapies, which are highly toxic to all cells and can induce DNA damage in healthy cells, leading to secondary cancer generation.
with ZNF423
, Polymerase (DNA directed), alpha 1, RELA
, XRCC1
, POLA2
, P53
, MYBL2
and Aprataxin
.
Enzyme
Enzymes are proteins that catalyze chemical reactions. In enzymatic reactions, the molecules at the beginning of the process, called substrates, are converted into different molecules, called products. Almost all chemical reactions in a biological cell need enzymes in order to occur at rates...
that in humans is encoded by the PARP1 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
PARP1 works:- By modifying nuclear proteins by poly ADP-ribosylationADP-ribosylationADP-ribosylation is the addition of one or more ADP-ribose moieties to a protein. These reactions are involved in cell signaling and the control of many cell processes, including DNA repair and apoptosis.-ADP-ribosylation enzymes:...
. - In conjunction with BRCABRCABRCA can refer to one of several things:*BRCA1 and BRCA2, a pair of genes involved in breast cancer. See BRCA mutation*British Radio Car Association – an organisation governing all types of radio controlled car racing in the United Kingdom....
, which acts on double strands; members of the PARP family act on single strands; or, when BRCA fails, PARP takes over those jobs as well.
PARP1 is involved in:
- Differentiation, proliferation, and tumor transformation
- Normal or abnormal recovery from DNA damage
- May be the site of mutation in Fanconi anemiaFanconi anemiaFanconi anemia is a genetic disease with an incidence of 1 per 350,000 births, with a higher frequency in Ashkenazi Jews and Afrikaners in South Africa.FA is the result of a genetic defect in a cluster of proteins responsible for DNA repair...
- May participate in the pathophysiology of type I diabetes.
PARP1 is activated by:
- Helicobacter pyloriHelicobacter pyloriHelicobacter pylori , previously named Campylobacter pyloridis, is a Gram-negative, microaerophilic bacterium found in the stomach. It was identified in 1982 by Barry Marshall and Robin Warren, who found that it was present in patients with chronic gastritis and gastric ulcers, conditions that were...
in the development and proliferation of gastric cancer.
Role in DNA damage repair
PARP1 has a role in repair of single-stranded DNA (ssDNA) breaks. Knocking down intracellular PARP1 levels with siRNASírna
Sírna Sáeglach , son of Dian mac Demal, son of Demal mac Rothechtaid, son of Rothechtaid mac Main, was, according to medieval Irish legend and historical tradition, a High King of Ireland...
or inhibiting PARP1 activity with small molecules reduces repair of ssDNA breaks. In the absence of PARP1, when these breaks are encountered during DNA replication
DNA replication
DNA replication is a biological process that occurs in all living organisms and copies their DNA; it is the basis for biological inheritance. The process starts with one double-stranded DNA molecule and produces two identical copies of the molecule...
, the replication fork
Replication fork
The replication fork is a structure that forms within the nucleus during DNA replication. It is created by helicases, which break the hydrogen bonds holding the two DNA strands together. The resulting structure has two branching "prongs", each one made up of a single strand of DNA...
stalls, and double-strand DNA (dsDNA) breaks accumulate. These dsDNA breaks are repaired via homologous recombination
Homologous recombination
Homologous recombination is a type of genetic recombination in which nucleotide sequences are exchanged between two similar or identical molecules of DNA. It is most widely used by cells to accurately repair harmful breaks that occur on both strands of DNA, known as double-strand breaks...
(HR) repair, a potentially error-free repair mechanism. For this reason, cells lacking PARP1 show a hyper-recombinagenic phenotype (e.g., an increased frequency of HR), which has also been observed in vivo
In vivo
In vivo is experimentation using a whole, living organism as opposed to a partial or dead organism, or an in vitro controlled environment. Animal testing and clinical trials are two forms of in vivo research...
in mice using the pun assay. Thus, if the HR pathway is functioning, PARP1 null mutants (cells without functioning PARP1) do not show an unhealthy phenotype, and in fact, PARP1 knockout mice show no negative phenotype and no increased incidence of tumor formation.
Interaction with BRCA1 and BRCA2
However, both BRCA1BRCA1
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...
and BRCA2
BRCA2
BRCA2 is a protein that in humans is encoded by the BRCA2 gene.BRCA2 orthologs have been identified in most mammals for which complete genome data are available....
are at least partially necessary for the HR pathway to function. Therefore, cells that are deficient in BRCA1 or BRCA2 have been shown to be highly sensitive to PARP1 inhibition or knock-down, resulting in cell death by apoptosis
Apoptosis
Apoptosis is the process of programmed cell death that may occur in multicellular organisms. Biochemical events lead to characteristic cell changes and death. These changes include blebbing, cell shrinkage, nuclear fragmentation, chromatin condensation, and chromosomal DNA fragmentation...
, in stark contrast to cells with at least one good copy of both BRCA1 and BRCA2. Many breast cancers have defects in the BRCA1/BRCA2 HR repair pathway due to mutations in either BRCA1 or BRCA2, or other essential genes in the pathway (the latter termed cancers with "BRCAness"). Tumors with BRCAness are hypothesized to be highly sensitive to PARP1 inhibitors, and it has been demonstrated in mice that these inhibitors can both prevent BRCA1/2-deficient xenografts from becoming tumors and eradicate tumors having previously formed from BRCA1/2-deficient xenografts.
Application to cancer therapy
It is hypothesized that PARP1 inhibitorPARP inhibitor
PARP inhibitors are a group of pharmacological inhibitors of the enzyme poly ADP ribose polymerase . They are developed for multiple indications; the most important is the treatment of cancer...
s may prove highly effective therapies for cancers with BRCAness, due to the high sensitivity of the tumors to the inhibitor and the lack of deleterious effects on the remaining healthy cells with functioning BRCA HR pathway. This is in contrast to conventional chemotherapies, which are highly toxic to all cells and can induce DNA damage in healthy cells, leading to secondary cancer generation.
Interactions
PARP1 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 ZNF423
ZNF423
Zinc finger protein 423 is a protein that in humans is encoded by the ZNF423 gene.The protein encoded by this gene is a nuclear protein that belongs to the family of Kruppel-like C2H2 zinc finger proteins. It functions as a DNA-binding transcription factor by using distinct zinc fingers in...
, Polymerase (DNA directed), alpha 1, RELA
RELA
Transcription factor p65 is a protein that in humans is encoded by the RELA gene.-Interactions:RELA has been shown to interact with NFKBIB, ETHE1, NFKBIE, RFC1, TRIB3, CREB binding protein, Neutrophil cytosolic factor 1, Glucocorticoid receptor, MTPN, BRCA1, C-Fos, POU2F1, BTRC, TATA-binding...
, 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:...
, POLA2
POLA2
DNA polymerase alpha subunit B is an enzyme that in humans is encoded by the POLA2 gene.-Further reading:...
, P53
P53
p53 , is a tumor suppressor protein that in humans is encoded by the TP53 gene. p53 is crucial in multicellular organisms, where it regulates the cell cycle and, thus, functions as a tumor suppressor that is involved in preventing cancer...
, MYBL2
MYBL2
Myb-related protein B is a protein that in humans is encoded by the MYBL2 gene.-Interactions:MYBL2 has been shown to interact with Retinoblastoma-like protein 1, Cyclin A1, EP300, CREB-binding protein, CDK9, Cyclin-dependent kinase inhibitor 1C and PARP1.-Further reading:...
and Aprataxin
Aprataxin
Aprataxin is a protein that in humans is encoded by the APTX gene.-Interactions:Aprataxin has been shown to interact with XRCC1, PARP1 and P53.-External links:**...
.
See also
- Poly ADP ribose polymerasePoly ADP ribose polymerasePoly 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...
- PARP inhibitorPARP inhibitorPARP inhibitors are a group of pharmacological inhibitors of the enzyme poly ADP ribose polymerase . They are developed for multiple indications; the most important is the treatment of cancer...
class of investigational anti-cancer drugs - olaparibOlaparibOlaparib is a chemotherapeutic agent developed by KuDOS Pharmaceuticals and later by Astra Zeneca. It is an inhibitor of PARP, an enzyme involved in DNA repair. It acts against cancers in people with hereditary BRCA1 or BRCA2 mutations, which includes many ovarian, breast and prostate cancers...
a PARP inhibitor.