Poly ADP ribose polymerase
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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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[edit] 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.
[edit] Functions
[edit] Role in forming polymer of ADP-ribose (PAR)
These enzymes have the capacity to polymerize ADP-ribose (PAR) from NAD (nicotinamide adenine dinucleotide).
The polymer can be degraded by a specialized enzyme named PARG (poly(ADP-ribose) glycohydrolase).
Another newly discovered enzyme can degrade PAR and is unrelated to PARG. This enzyme is called ARH3 (ADPRHL2).
[edit] 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.
[edit] 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.
[edit] 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.
[edit] 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 .
[edit] 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
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