A new study published in Science is shedding light on the molecular details of PARP-1, a DNAdamage-detecting enzyme that when inhibited has been shown to beeffective in fighting cancer and other diseases. The investigation led by John M. Pascal, Ph.D., an assistantprofessor in the Department of Biochemistry and Molecular Biologyat Thomas Jefferson University and Jefferson's Kimmel CancerCenter, revealed new target sites - including specialized "zincfinger" domains - for drugs aiming to stop PARP-1 activity. The idea for this area of research is to identify more specificPARP-1 inhibitors that achieve a targeted inhibition, with lesspotential for side effects. Drugs inhibiting PARP-1 have also beenproven effective in treating inflammation and cardiac disease. |
"PARP-1 has been identified as a valuable target, but what'sspecial about it? What really are its weak points in the way itgets activated?" said Dr. Pascal. "We wanted to define a structuraland mechanistic framework to better understand how to specificallyinhibit PARP-1." The weak points were found to be multi-domain interfaces that areuniquely found in PARP-1. What researchers now know is thatmultiple domains of PARP-1 come together and bind to DNA damage,and this "communication" between domains is essential for DNAdamage-dependent PARP-1 activity.
PARP-1 is a protein that detects and responds to breaks in thestructure of DNA, a potentially lethal form of damage to ourgenetic information. If PARP-1 activity is impaired, DNA strandbreaks are not repaired and instead are converted into moredangerous types of DNA damage. In normal tissue, a repair mechanismcalled homologous recombination picks up the slack and fixes thedamaged DNA. However, in cancers that carry the BRCA mutation, likecertain breast and ovarian cancers , homologous recombination is inactivated. Therefore, the cancerouscells have become dependent on the role PARP-1 plays in DNA repair.
In a more general scenario, inhibiting PARP-1 has been successfulwhen combined with DNA-damaging drugs because it enhances theapoptotic activity of these drugs. In other words, it helps halttumor growth. Today, many PARP-1 inhibitors being tested in preclinical andclinical studies target the catalytic active site. But thisapproach is limiting because the catalytic site is similar to thosefound in other PARP-like proteins that carry out other essentialcellular functions, thus increasing the potential for off targetside effects.
"What was exciting in our structure of PARP-1 is that there arespecialized sites on the protein that can be inhibited; you caneffectively kill catalytic activity without having to touch thecatalytic active site," said Dr. Pascal. Using X-ray crystallography, researchers studied the interactionamongst the component domains of PARP-1 and their combined role inbinding to DNA damage. The PARP-1/DNA structure revealed a networkof interdomain contacts formed upon DNA binding.
These domains haveto come together and assemble, the researchers found, to havecatalytic activity. "Our work indicates that we should be looking for inhibitors thatprevent these domains from coming together," Dr. Pascal said."Rather than screen for inhibitors with catalytic activity as areadout, we can screen for inhibitors that disrupt thecommunication between the PARP-1 domains, which would in turn shutdown catalytic activity." Closer attention to these specialized domains could inspire thedesign of a new class of PARP inhibitors. "Dr.
Pascal's structural and biochemical characterization revealshow recognition of DNA damage and communication between domainscontrol the activity of PARP-1," said Barbara Gerratana, Ph.D., whooversees enzyme catalysis grants at the National Institutes ofHealth's National Institute of General Medical Sciences, whichpartially supported the study. "This work is a major breakthroughin understanding an enzyme essential for regulation of cellproliferation and a promising target for cancer therapeutics." Additional References Citations.
We are high quality suppliers, our products such as Custom Injection Molding , Zinc Alloy Die Casting Mould Manufacturer for oversee buyer. To know more, please visits Custom Injection Molding.
Related Articles -
Custom Injection Molding, Zinc Alloy Die Casting Mould Manufacturer,