Poly(ADP-ribose) polymerase-1

Poly(ADP-ribose) polymerase-1 (PARP-1) is an enzyme that in humans is encoded by the PARP1 gene. It is one of the PARP family members and plays a key role in the repair of DNA damage and the maintenance of genomic stability. PARP-1 is involved in a variety of cellular processes, including DNA repair, genomic stability, transcription, apoptosis, and cell cycle regulation.

Function

PARP-1 uses NAD+ as a substrate to transfer ADP-ribose units to target proteins, a process known as ADP-ribosylation. This modification can affect the function of the modified proteins and is critical in the response to DNA damage. Specifically, PARP-1 is activated by strand breaks in DNA, and its activity is crucial for the repair of single-strand breaks (SSBs) through the base excision repair (BER) pathway. If these breaks are not repaired, they can lead to double-strand breaks (DSBs) during DNA replication, which are more challenging to repair and can lead to cell death or cancer.

Clinical Significance

PARP-1 is a target for cancer therapy, especially in cancers with defects in other DNA repair mechanisms, such as BRCA1 or BRCA2 mutations in breast and ovarian cancers. Inhibitors of PARP-1, known as PARP inhibitors, can lead to the accumulation of DNA damage in cancer cells, ultimately causing their death. This therapeutic approach is an example of synthetic lethality.

PARP Inhibitors

PARP inhibitors are a class of pharmacological inhibitors that have shown promise in cancer treatment, particularly for cancers with BRCA mutations. By inhibiting PARP-1, these drugs prevent the repair of single-strand breaks, leading to the accumulation of DNA damage and cell death in cancer cells. Examples of PARP inhibitors include olaparib, rucaparib, and niraparib.

Genetics

The PARP1 gene is located on the long (q) arm of chromosome 1 at position 22. The gene spans over 47 kb and consists of 23 exons. Mutations in this gene have been associated with susceptibility to cancer, as well as with differential responses to chemotherapy.

Research Directions

Research on PARP-1 continues to explore its roles beyond DNA repair, including its involvement in transcriptional regulation, chromatin remodeling, and cell death pathways. Understanding the multifaceted roles of PARP-1 could lead to novel therapeutic strategies for cancer and other diseases.

See Also

• DNA repair
• Genomic stability
• Apoptosis
• Cell cycle
• PARP family
• PARP inhibitors