Stains
PARP

Authors: Emeka Enwere, M.D., Thakur Satbir Singh, Ph.D. (see Authors page)

Revised: 28 July 2016, last major update July 2016

Copyright: (c) 2002-2016, PathologyOutlines.com, Inc.

PubMed Search: PARP [title]

Definition / General
  • Poly (ADP ribose) polymerase1 (PARP1) is a nuclear chromatin associated enzyme that plays key roles in many cellular processes, including DNA damage detection and repair, regulation of chromatin structure and the control of gene expression, as well as differentiation, proliferation and tumor transformation (GeneCards)
  • It is one of the most abundant proteins in a mammalian cell and acts by modifying various nuclear proteins by poly(ADP-ribosyl)ation (PARylation)
Essential Features
  • Member of the PARP superfamily which consists of 17 proteins in humans
  • Most of these enzymes catalyze the formation of polymeric ADP ribosyl adducts ("PARylation") on target proteins, using nicotinamide adenine dinucleotide (NAD+) molecules as donors of ADP ribose groups
  • Targets for PARP1 enzymatic activity include histones, the linker histone H1 and a variety of transcription factors (Genes Dev 2005;19:1951, Biochem J 1999;342:249).
  • Due to its ability to interact with genomic DNA and chromatin, and PARylate a variety of nuclear proteins, PARP1 can regulate various cellular signaling pathways
  • PARP activation is an immediate cellular response to metabolic, chemical or radiation induced DNA damage (Proteome Sci 2010;8:22)
  • In this context, PARP1 is an important regulator of DNA base excision repair, which is a key repair mechanism determining the responsiveness of cancer cells to alkylating drugs such as temozolomide and ionizing radiation
  • In the absence of the DNA repair enzymes BRCA1 or BRCA2, cells rely extensively on PARP1 regulated repair pathways to maintain genomic integrity; pharmacological inhibition of PARP1 thereafter leads to failure of DNA repair and apoptosis
  • This has led to the development of various PARP inhibitors to treat cancer, ischemic injury and cardiovascular diseases (Drug News Perspect 2007;20:171)
  • Cleaved by caspases during apoptosis; cleaved PARP is an indicator of apoptotic response (Curr Opin Cell Biol 2008;20:294)
Terminology
    Also known as:
  • ADP-Ribosyltransferase (NAD+; Poly (ADP-Ribose) Polymerase); Poly (ADP-Ribose) Polymerase Family, Member 1
  • NAD (+) ADP-Ribosyltransferase 1; Poly (ADP-Ribose) Synthase 1
  • ADP-Ribosyltransferase Diphtheria Toxin-Like 1; ADPRT1, ADPRT, ARTD1
  • PPOL, Poly (ADP-Ribose) Polymerase 1
  • ADP-Ribosyltransferase NAD (+) , Poly (ADP-Ribosyl) Transferase
  • Poly (ADP-Ribose) Polymerase, Poly (ADP-Ribose) Synthetase
  • PADPRT-1, ADPRT1
  • References: GeneCards
  • Sites
    Pathophysiology
    • Inhibition of PARP enzymatic activity in BRCA1 and BRCA2 mutant cells results in DNA lesions which lead to chromosomal instability, cell cycle arrest and apoptosis (Nature 2005;434:917); PARP1 inhibition using olaparib in cancer patients bearing BRCA1 and BRCA2 mutations results in complete response with fewer adverse effects than conventional chemotherapy (N Engl J Med 2009;361:123)
    • Can regulate gene expression epigenetically by directly influencing DNA methylation patterns by controlling transcription and activity of DNA methyltransferase-1 (PLoS One 2012;7:e46927)
    • In reprogramming of somatic cells to induced pluripotent stem cells, PARP1 and Tet2 maintain active histone architecture and promote binding of reprogramming proteins like Oct4 (Nature 2012;488:652)
    • In PARP1 null mice, increased frequency of recombination, gene amplification and sister chromatid exchange were observed upon exposure to genotoxic stress as compared to wildtype mice (Proc Natl Acad Sci U S A 1999;96:13191); this is in spite of the presence of 15 other PARP proteins in mice, which supply a measure of redundancy in the absence of PARP1
    • Helicobacter pylori infection activates PARP1 activity in the infected host which can modulate various signaling pathways (Rev Esp Enferm Apar Dig 1989;75:91)
    • Increased levels of PARP1 promote leukemia with activated tyrosine kinases by following error prone DNA repair pathway using DNA microhomologies (Mol Cancer Res 2015;13:699)
    • Found to be overexpressed and associated with poor survival in cancers like neuroblastoma, lymphoma and early stage breast cancers (Mol Cancer Res 2015;13:470, Am J Hematol 1991;37:223, Ann Oncol 2012;23:1156)
    • Increased PARP activity has been positively correlated with life span which may be due to increased genomic stability (Proc Natl Acad Sci U S A 1992;89:11764)
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    Positive Stains
    • Ubiquitously expressed at high levels in most tissues
    Negative Stains
    • Hair follicle, nasal respiratory epithelium and cerebral cortex express medium to low levels
    Additional References