Poly (ADP-ribose) polymerase (PARP) is a protein involved in a number of cellular processes involving mainly DNA repair and programmed cell death.
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Members of PARP family
The PARP family comprises 17 members (10 putative). They have all very different structures and functions in the cell.
- PARP1, PARP2, VPARP (PARP4), Tankyrase-1 and 2 (PARP-5a or TNKS, and PARP-5b or TNKS2) have a confirmed PARP activity.
- Others include PARP3, PARP6, TIPARP (or "PARP7"), PARP8, PARP9, PARP10, PARP11, PARP12, PARP14, PARP15, and PARP16.
Functions
PARP enzymes are essential in a number of cellular functions[1], including expression of inflammatory genes[2]: PARP1 is required for the induction of ICAM-1 gene expression by smooth muscle cells, in response to TNF[3].
Role in repairing DNA nicks
One important function of PARP is assisting in the repair of single-strand DNA nicks. It binds sites with single strand breaks through its N-terminal zinc fingers and will recruit XRCC1, DNA ligase III, DNA polymerase beta and a kinase to the nick. This is called base excision repair (BER). PARP-2 has been shown to oligomerize with PARP-1 and therefore is also implicated in BER. The oligomerization has also been shown to stimulate PARP catalytic activity. PARP-1 is also known for its role in transcription through remodelling of chromatin by PARylating histones and relaxing chromatin structure, thus allowing transcription complex to access genes.
Role of tankyrases
The tankyrases are PARPs that comprise ankyrin repeats, oligomerization domain (SAM) and a PARP catalytic domain (PCD). Tankyrases are also known as PARP-5a and PARP-5b. They were named for their interaction with the telomere associated TRF1 proteins and ankyrin repeats. They may allow the removal of telomerase-inhibiting complexes from chromosome ends to allow for telomere maintenance. Through their SAM domain and ANKs they can oligomerize and interact with many other proteins, such as TRF1, TAB182 (TNKS1BP1), GRB14, IRAP, NuMa, EBNA-1, and Mcl-1. They have multiple roles in the cell, vesicular trafficking through its interaction in GLUT4 vesicle (GSVs) with insulin responsive amino peptidase (IRAP). It also plays a role in spindle assembly through its interaction with nuclear mitotic apparatus (NuMa) therefore allowing bipolarity. In the absence of TNKs mitosis arrest is observed in pre-anaphase through Mad2 kinetochore checkpoint. TNKs can also PARsylate Mcl-1L and Mcl-1S and inhibit both their pro and anti apoptotic function. Relevance of this is not yet known.
Role in cell death
Upon DNA cleavage by enzymes involved in cell death (such as caspases), PARP can deplete the ATP of a cell in an attempt to repair the damaged DNA. ATP depletion in a cell leads to lysis and cell death. PARP also has the ability to directly induce apoptosis, via the production of PAR, which stimulates mitochondria to release AIF. This mechanism appears to be caspase-independent.[4]
Role in Epigenetic DNA modification
PARP mediated post-translational modification of proteins such as CTCF can affect the amount of DNA methylation at CpG dinucleotides. This regulates the insulator features of CTCF can differentially mark the copy of DNA inherited from either the maternal or paternal DNA through the process known as genomic imprinting. PARP has also been proposed to affect the amount of DNA methylation by directly binding to the DNA methyltransferase DNMT-1 after attaching poly ADP-ribose chains to itself after interaction with CTCF and affecting DNMT1's enzymatic activity .
References
- ^ Piskunova TS, Yurova MN, Ovsyannikov AI, Semenchenko AV, Zabezhinski MA, Popovich IG, Wang ZQ, Anisimov VN. Deficiency in Poly(ADP-ribose) Polymerase-1 (PARP-1) Accelerates Aging and Spontaneous Carcinogenesis in Mice. Curr Gerontol Geriatr Res. 2008:754190. Epub 2008 Apr 14.PMID: 19415146
- ^ Espinoza LA, Smulson ME, Chen Z. Prolonged poly(ADP-ribose) polymerase-1 activity regulates JP-8-induced sustained cytokine expression in alveolar macrophages. Free Radic Biol Med. 2007 May 1;42(9):1430-40. Epub 2007 Feb 1.PMID: 17395016
- ^ Zerfaoui M, Suzuki Y, Naura AS, Hans CP, Nichols C, Boulares AH. Nuclear translocation of p65 NF-kappaB is sufficient for VCAM-1, but not ICAM-1, expression in TNF-stimulated smooth muscle cells: Differential requirement for PARP-1 expression and interaction. Cell Signal. 2008 Jan;20(1):186-94. Epub 2007 Oct 12. PMID: 17993261
- ^ Apoptosis-inducing factor mediates poly(ADP-ribose) (PAR) polymer-induced cell death Seong-Woon Yu, Shaida A. Andrabi, Hongmin Wang, No Soo Kim*,Guy G. Poirier, Ted M. Dawson, Valina L. Dawson PNAS November 28, 2006 vol. 103 no. 48 18314-18319
External links
- Entry for a PARP immunoassay at bioreagents.com
- PARP - Poly (ADP-ribose) polymerase at inotekcorp.com
- The PARP Link Homepage at parplink.u-strasbg.fr
- MeSH Poly+ADP+Ribose+Polymerase
- Parp Inhibitors Information Site
See also
- PARP inhibitor class of anti-cancer agents
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