Poly (ADP-ribose) polymerase
Poly (ADP-ribose) polymerase (PARP) is a family of proteins involved in a number of cellular processes such as DNA repair, genomic stability, and programmed cell death.
This is integral in a programmed cell death model based on caspase cleavage inhibition of PARP.
[citation needed] The main role of PARP (found in the cell nucleus) is to detect and initiate an immediate cellular response to metabolic, chemical, or radiation-induced single-strand DNA breaks (SSB) by signaling the enzymatic machinery involved in the SSB repair.
[citation needed] Once PARP detects a SSB, it binds to the DNA, undergoes a structural change, and begins the synthesis of a polymeric adenosine diphosphate ribose (poly (ADP-ribose) or PAR) chain, which acts as a signal for the other DNA-repairing enzymes.
[4] But more recently it was suggested that inhibition of hexokinase activity leads to defects in glycolysis (Andrabi, PNAS 2014).
[citation needed] One important function of PARP is assisting in the repair of single-strand DNA nicks.
[10] PARP activity (which is mainly due to PARP1) measured in the permeabilized mononuclear 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.
[12] 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,[13] again indicating a linkage between longevity and repair capability.
They have multiple roles in the cell, like vesicular trafficking through its interaction in GLUT4 vesicles with insulin-responsive aminopeptidase (IRAP).
[16][17] PARP also has the ability to induce programmed cell death, via the production of PAR, which stimulates mitochondria to release AIF.
[19] ADP-ribose polymers, either free or PARP1 bound, are able to inhibit DNA methyltransferase activity at CpG sites.
[20] Thus, CTCF is involved in the cross-talk between poly(ADP-ribosyl)ation and DNA methylation, an important epigenetic regulatory factor.
[19] A substantial body of preclinical and clinical data has accumulated with PARP inhibitors in various forms of cancer.
Thus, PARP inhibitors of various types (e.g. olaparib) for BRCA mutant breast and ovarian cancers can extend beyond these tumors if appropriate biomarkers can be developed to identify HRR defects.
Besides degradation, there is recent evidence about reversible downregulation mechanisms for PARP, among these an "autoregulatory loop", which is driven by PARP1 itself and modulated by the YY1 transcription factor.
The putative mechanism of PCD activation via PARP inactivation relies on the separation of the DNA-binding region and the auto-modification domain.
[citation needed] Roles of poly(ADP-ribosyl)ation in plant responses to DNA damage, infection, and other stresses have been studied.
