Poly [ADP-ribose] polymerase 1

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Poly [ADP-ribose] polymerase 1 (PARP1) is a multifunctional enzyme involved in various cellular processes, including DNA repair, transcriptional regulation, chromatin remodeling, and cell death. It serves as a key player in maintaining genomic stability and cellular homeostasis. PARP1 is one of a family of enzymes that catalyze the transfer of ADP-ribose units from nicotinamide adenine dinucleotide (NAD+) to target proteins, a process known as poly-ADP ribosylation.

Structure

PARP1 is a nuclear protein consisting of several functional domains, including a DNA-binding domain, an automodification domain, a catalytic domain, and a nuclear localization signal. The DNA-binding domain of PARP1 allows it to recognize and bind to damaged DNA, initiating the process of DNA repair. The automodification domain is responsible for the self-modification of PARP1 through poly-ADP ribosylation. The catalytic domain contains the enzymatic activity of PARP1, catalyzing the transfer of ADP-ribose units to target proteins.

Function

PARP1 plays a critical role in maintaining genomic stability by detecting and repairing DNA damage. It is involved in base excision repair, a process that corrects small DNA lesions, such as single-strand breaks and oxidized bases. PARP1 also promotes the recruitment of DNA repair factors to the site of DNA damage, facilitating the repair process. In addition to its role in DNA repair, PARP1 regulates gene expression by modifying chromatin structure and interacting with transcription factors.

Mechanism

The enzymatic activity of PARP1 is activated upon binding to damaged DNA, triggering the synthesis of poly-ADP ribose chains on target proteins. This post-translational modification regulates the function of target proteins, influencing various cellular processes. PARP1 also undergoes automodification, leading to the formation of branched poly-ADP ribose chains on itself. This self-modification process regulates the activity of PARP1 and serves as a signaling mechanism in response to DNA damage.

Regulation

The activity of PARP1 is tightly regulated to maintain cellular homeostasis. PARP1 activity is modulated by various factors, including the availability of NAD+, the presence of DNA damage, and the interaction with regulatory proteins. Inhibition of PARP1 activity has been shown to sensitize cancer cells to DNA-damaging agents, making PARP1 an attractive target for cancer therapy. Several PARP inhibitors have been developed and are currently used in the treatment of cancer.

Applications

PARP1 has emerged as a promising target for cancer therapy due to its role in DNA repair and cell survival. PARP inhibitors have been approved for the treatment of breast, ovarian, and prostate cancers, particularly in patients with mutations in DNA repair genes, such as BRCA1 and BRCA2. These inhibitors work by blocking the enzymatic activity of PARP1, leading to the accumulation of DNA damage and cell death in cancer cells. In addition to cancer therapy, PARP1 inhibitors have shown potential in other diseases, such as neurodegenerative disorders and inflammatory conditions.

Conclusion

PARP1 is a critical enzyme with diverse functions in maintaining genomic stability, gene expression, and cellular signaling. Its role in DNA repair and cell survival makes it an attractive target for cancer therapy, with PARP inhibitors showing promising results in clinical trials. Further research into the regulation and function of PARP1 may lead to the development of new therapeutic strategies for the treatment of cancer and other diseases.