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.

Members of PARP family

The PARP family comprises 17 members (10 putative). They have all very different structures and functions in the cell.

Functions

Role in forming polymer of ADP-ribose (PAR)

These enzymes have the capacity to make a polymer of 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).

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. Through their SAM domain and ANKs they can oligomerize and interact with many other proteins, such as TAB182 (TNKS1BP1), GRB14, IRAP, NuMa, EBNA-1, and Mcl-1. They have multiple roles in the cell, vesicular trafficing 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.

External links

de:PARP-1 Inhibitor


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