PARP Primer

What are PARPs and their role in biology?

Poly(ADP-ribose) polymerases (PARPs) are a family of 17 enzymes that regulate fundamental cellular processes including gene expression, protein degradation, and multiple cellular stress responses. PARPs alter the function of target proteins by post-translational modification using nicotinamide adenine dinucleotide (NAD+), an essential metabolic co-factor found in all living cells.

 

What are the different kinds of PARPs?

PARPs can be classified based upon the type of modification made to target proteins.

  • polyPARPs modify their protein targets with large polymers called poly(ADP-ribose) or PAR. This large and highly charged attachment creates a protein recruitment scaffold that directs proteins to function at specific sites within the cell.
  • monoPARPs modify their targets with single units of ADP-ribose called mono(ADP-ribose), or MAR, that act as on-off switches to regulate protein function.
  • enzymatically inactive PARPs regulate target proteins through other mechanisms that do not involve direct modification.

 

MonoPARPs have a unique function in post-translational modification of target proteins, distinct from the previously-established role of polyPARPs.

 

What is the role of PARPs in cellular pathways?

Due to the large size of the PARP family of proteins and its diverse activity and different target proteins, PARPs are involved in many key cellular pathways and have important roles in DNA repair, transcription, heat shock and cytoplasmic stress response, cell division, RNA processing and more.

 

What is PARP1 and its role as a cancer target?

PARP1 is the first member of the PARP family that has been shown to be an effective cancer target. PARP1 is the best studied PARP and functions in DNA damage repair, a process that is often defective in cancers. The approved drug Lynparza (olaparib) is a PARP1 inhibitor that kills those cancers that possess defects in DNA damage repair (for example, mutations in the BRCA gene).  Most of the oncology focus has been on PARP1 and other polyPARPs.

 

What is known about monoPARPs?

Historically much of the attention on the PARP family has been focused on PARP1 and other polyPARPs, due in part to the relative ease in detecting the PAR modification. Recently, data are emerging about monoPARPs and their role distinct from polyPARPs. There are 11 monoPARPs and several have been shown to regulate cancer cells’ stress response mechanism to promote cell survival. The specific target proteins and functions of monoPARPs are currently being elucidated and represent an important new field for innovative cancer drug development due to their fundamental role in cancer cell survival and other diseases including inflammatory and neurodegenerative diseases.

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