PARP1

Poly [ADP-ribose] polymerase 1 (PARP-1) also known as NAD+ ADP-ribosyltransferase 1 or poly[ADP-ribose] synthase 1 is an is_associated_with::enzyme that in humans is encoded by the PARP1 is_associated_with::gene.

Function
PARP1 works:
 * By modifying nuclear proteins by poly is_associated_with::ADP-ribosylation.
 * In conjunction with BRCA, 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 is_associated_with::Fanconi anemia
 * May participate in the pathophysiology of is_associated_with::type I diabetes.

PARP1 is activated by:
 * is_associated_with::Helicobacter pylori in the development and proliferation of is_associated_with::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 is_associated_with::siRNA or inhibiting PARP1 activity with small molecules reduces repair of ssDNA breaks. In the absence of PARP1, when these breaks are encountered during is_associated_with::DNA replication, the is_associated_with::replication fork stalls, and double-strand DNA (dsDNA) breaks accumulate. These dsDNA breaks are repaired via is_associated_with::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 is_associated_with::in vivo in mice using the is_associated_with::pun assay. Thus, if the HR pathway is functioning, PARP1 is_associated_with::null mutants (cells without functioning PARP1) do not show an unhealthy phenotype, and in fact, PARP1 is_associated_with::knockout mice show no negative phenotype and no increased incidence of tumor formation.

PARP1 also has a role in is_associated_with::microhomology-mediated end joining (MMEJ) repair of double strand breaks. It is one of 6 enzymes required for this error prone DNA repair pathway. PARP1 is over-expressed in tyrosine kinase-activated leukemias, in neuroblastoma, in testicular and other germ cell tumors, and in Ewing’s sarcoma,

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 is_associated_with::cancer syndromes). (Also see is_associated_with::DNA repair-deficiency disorder.) 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), lead to mutations and cancer. However, PARP1 mediated MMEJ repair is highly inaccurate, so in this case, over-expression, rather than under-expression, apparently leads to cancer.

Interaction with BRCA1 and BRCA2
However, both is_associated_with::BRCA1 and is_associated_with::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 is_associated_with::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 is_associated_with::xenografts from becoming tumors and eradicate tumors having previously formed from BRCA1/2-deficient xenografts.

Application to cancer therapy
It is hypothesized that PARP1 inhibitors 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 is_associated_with::chemotherapies, which are highly toxic to all cells and can induce DNA damage in healthy cells, leading to secondary cancer generation.

Aging
PARP activity (which is mainly due to PARP1) measured in the permeabilized mononuclear is_associated_with::leukocyte blood cells of thirteen mammalian species (rat, guinea pig, rabbit, marmoset, sheep, pig, cattle, pigmy chimpanzee, horse, donkey, gorilla elephant and man) correlates with maximum lifespan of the species. is_associated_with::Lymphoblastoid cell lines established from blood samples of humans who were centenarians (100 years old or older) have significantly higher PARP activity than cell lines from younger (20 to 70 years old) individuals. The Wrn protein is deficient in persons with is_associated_with::Werner syndrome, a human premature aging disorder. PARP1 and Wrn proteins are part of a complex involved in the processing of DNA breaks. These findings indicate a linkage between longevity and PARP-mediated DNA repair capability. Furthermore these observations suggest that PARP repair activity contributes to mammalian longevity, consistent with the is_associated_with::DNA damage theory of aging.

PARP1 appears to be resveratrol's primary functional target through its interaction with the tyrosyl tRNA synthetase (TyrRS).

Interactions
PARP1 has been shown to interact with:
 * APTX,
 * is_associated_with::MYBL2
 * is_associated_with::RELA,
 * is_associated_with::P53,
 * POLA1,
 * is_associated_with::POLA2,
 * is_associated_with::XRCC1, and
 * is_associated_with::ZNF423.