PARP1

Poly (ADP-ribose) polymerase 1 (PARP1)

Poly (ADP-ribose) polymerase 1, commonly abbreviated as PARP1, is a crucial enzyme involved in a variety of cellular processes, including DNA repair, genomic stability, and programmed cell death. PARP1 is a member of the PARP family of proteins, which are involved in the post-translational modification of proteins through the addition of poly (ADP-ribose) chains.

Structure

PARP1 is a large protein composed of several domains, each contributing to its function:

• DNA-binding domain: This domain allows PARP1 to recognize and bind to sites of DNA damage.
• Automodification domain: This region is responsible for the self-modification of PARP1, which is crucial for its release from DNA and regulation of its activity.
• Catalytic domain: The catalytic domain is responsible for the transfer of ADP-ribose units from NAD+ to target proteins, forming poly (ADP-ribose) chains.

Function

PARP1 plays a pivotal role in the repair of single-strand breaks (SSBs) in DNA. Upon detecting DNA damage, PARP1 binds to the site and catalyzes the addition of poly (ADP-ribose) chains to itself and other proteins, facilitating the recruitment of DNA repair machinery. This process is essential for maintaining genomic stability and preventing mutations that could lead to cancer.

PARP1 is also involved in:

• Regulation of chromatin structure: By modifying histones and other chromatin-associated proteins, PARP1 influences chromatin remodeling and gene expression.
• Cell death pathways: In response to severe DNA damage, PARP1 can promote cell death through mechanisms such as apoptosis and necrosis.

Clinical Significance

PARP1 has become a target for cancer therapy, particularly in tumors with defects in DNA repair pathways, such as BRCA1 and BRCA2 mutations. PARP inhibitors, such as olaparib, exploit the concept of "synthetic lethality" to selectively kill cancer cells while sparing normal cells.

Research and Development

Ongoing research is focused on understanding the broader roles of PARP1 in cellular physiology and its potential as a therapeutic target in various diseases beyond cancer, including neurodegenerative disorders and inflammatory conditions.

Also see

• DNA repair
• Apoptosis
• BRCA1
• BRCA2
• Olaparib