Poly (ADP-ribose) polymerase

ADP ribose

Poly (ADP-ribose) polymerase (PARP) is a family of proteins involved in a number of cellular processes such as DNA repair, genomic stability, and programmed cell death. The role of PARP, especially PARP-1, in DNA repair is to sense DNA strand breaks and signal for their repair.

Function

PARP proteins are involved in the repair of single-strand DNA breaks. Upon sensing a break in the DNA, PARP binds to the DNA and synthesizes a poly (ADP-ribose) chain as a signal for other DNA repairing proteins. This process is crucial for maintaining the integrity of the genome and preventing mutations that could lead to cancer. In addition to their role in DNA repair, PARPs also play a role in the regulation of transcription, chromatin structure, and cell death.

Mechanism

The mechanism of action of PARP involves the detection of DNA damage, after which it binds to the site of damage and recruits DNA repair enzymes. PARP uses NAD+ as a substrate to add ADP-ribose units to itself (auto-ribosylation) and to other target proteins. This modification changes the function of the proteins and facilitates the repair of DNA. When the damage is too severe, PARP can also facilitate cell death to prevent the propagation of damaged DNA.

Clinical Significance

PARP inhibitors are a class of drugs that inhibit the enzyme PARP. They are used in cancer therapy to exploit the concept of synthetic lethality. Cancer cells often have defects in the BRCA1 or BRCA2 genes, making them more reliant on PARP-mediated DNA repair. By inhibiting PARP, these drugs can increase DNA damage in cancer cells, leading to their death. PARP inhibitors have shown effectiveness in treating certain types of cancers, such as ovarian and breast cancers that have BRCA mutations.

PARP Inhibitors

Some examples of PARP inhibitors include Olaparib, Rucaparib, and Niraparib. These drugs have been approved for use in various cancers and are the subject of ongoing research to expand their use to other conditions.

Research Directions

Research on PARP continues to explore its roles beyond DNA repair, including its involvement in inflammation, neurodegeneration, and heart disease. Understanding the full range of PARP's functions and its interactions with other cellular pathways could lead to new therapeutic strategies for a variety of diseases.