Cysteine-aspartic proteases and Poly (ADP-ribose) polymerases (Caspases/PARP)

Cysteine-aspartic proteases (Caspases) and Poly (ADP-ribose) polymerases (PARP) are distinct enzyme families that play critical, interconnected roles in DNA damage response and programmed cell death. Caspases are proteases that act as the executioners of apoptosis, triggered by intrinsic or extrinsic pathways to systematically dismantle the cell (McIlwain et al., 2013) [3]. PARP enzymes, specifically PARP-1, are essential for identifying DNA single-strand breaks and initiating repair through the recruitment of the DNA repair machinery (Morales et al., 2014) [4]. A key regulatory link exists between them: during apoptosis, effector caspases cleave PARP-1 into 24 kDa and 89 kDa fragments, which inactivates the enzyme and conserves cellular energy for the completion of the death process (Lazebnik et al., 1994) [5]. In therapeutic contexts, PARP inhibitors are widely used to treat cancers with homologous recombination deficiencies, such as BRCA-mutated breast and ovarian cancers, by exploiting synthetic lethality (Robson et al., 2017) [6]. Caspase inhibitors have been explored as cytoprotective agents to prevent excessive cell loss in neurodegenerative diseases and inflammatory conditions, though they have faced significant hurdles in clinical efficacy (Talanian et al., 2000) [7].

Other names

Caspase familyPARP familyCysteine-aspartic proteasesPoly [ADP-ribose] polymerasePARP-1Caspase-3Caspase-8Caspase-9

PARP inhibitors block the repair of single-strand DNA breaks and trap PARP proteins on DNA, causing replication fork collapse and double-strand breaks that lead to death in BRCA-deficient cells (Lord & Ashworth, 2017) [1]. Caspase inhibitors bind to the active site of caspase enzymes, preventing the cleavage of downstream proteins required for apoptosis or cytokine maturation (Shalini et al., 2015) [2].