Abstract
Poly (ADP-ribose) polymerase (PARP) 1 is an essential molecule in DNA damage response by sensing DNA damage and docking DNA repair proteins on the damaged DNA site through a type of posttranslational modification, poly (ADP-Ribosyl)ation (PARylation). PARP inhibitors, which inhibit PARylation through competitively binding to NAD+ binding site of PARP1 and PARP2, have improved clinical benefits for BRCA mutated tumors, leading to their accelerated clinical application. However, the antitumor activities of PARP inhibitors in clinical development are different, due to PARP trapping activity beyond blocking PARylation reactions. In this review, we comprehensively address the current state of knowledge regarding the mechanisms of action of PARP inhibitors. We will also discuss the different effects of PARP inhibitors in combination with cytotoxic chemotherapeutic agents regarding the mechanism of regulating PARylation.
Highlights
All cells have more than tens of thousands of events that damage DNA in multiple ways, ranging from single base mismatches, bulky adducts in DNA bases, intra- and inter-strand DNA crosslinks, to single- and double-strand breaks (SSBs and DSBs) [1,2]
PARylation is the reaction of transferring ADP-ribose residues to target substrates by ADP-ribosyl transferase using NAD+. It rapidly recognizes multiple types of DNA damage, including SSBs, and is recruited to the damaged site to induce the recruitment of DNA damage responses (DDRs) molecules so that the poly (ADP-Ribose) polymerase (PARP), PARP1, PARP2, PARP3, PARP5a, and PARP5b, which are known as the major molecules of DDR, performs poly (ADP-ribose) (PAR) synthesis in humans [6]
Upon X-ray repair cross-complementing protein 1 (XRCC1) binding to DNA damage sites, the PAR formation is increased by sequestering poly (ADP-ribose) glycohydrolase (PARG) from the interaction with PARP1 and PARG, resulting in causing dissociation of PARP1 from DNA damage site and increasing repair signal transduction [26,27,28]
Summary
All cells have more than tens of thousands of events that damage DNA in multiple ways, ranging from single base mismatches, bulky adducts in DNA bases, intra- and inter-strand DNA crosslinks, to single- and double-strand breaks (SSBs and DSBs) [1,2] PARylation is the reaction of transferring ADP-ribose residues to target substrates by ADP-ribosyl transferase using NAD+ It rapidly recognizes multiple types of DNA damage, including SSBs, and is recruited to the damaged site to induce the recruitment of DDR molecules so that the poly (ADP-Ribose) polymerase (PARP), PARP1, PARP2, PARP3, PARP5a, and PARP5b, which are known as the major molecules of DDR, performs poly (ADP-ribose) (PAR) synthesis in humans [6]. The catalytic inhibition and trapping effects of PARP are tightly regulated, and the cytotoxicity of each mechanism can cause different reactivities. In this review, based on mechanisms of PARP, we intend to examine the difference of anti-tumor effect of the PARP inhibitors and the current aspect of the roles in combination treatment
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