PARP-1, the canonical representative of this superfamily has become the major focus of research due to its multifaceted roles in many cellular activities. The PARP family consists of 17 members which have different structures and diverse functions in cells. PARP-1, 2 and 3 can activate CNS immune responses by promoting astrocyte production of inflammatory cytokines like TNF-α, IL-1β, nitric oxide and the chemokine CCL2 after challenge with Staphylococcus aureus, a common CNS infectious agent. during atherogenesis) via its binding partner NF-κB. PARP-1 is also involved in modulating endothelial cell adhesion molecule expression (e.g. PARP-1 also interacts with, and modulates the function of several transcription factors including NF-κB, NFAT, E2F-1, and ELK-1. Gene expression is dysregulated in PARP-1 deficient fibroblasts and PARP-1 deficient mice are more susceptible to skin diseases reflecting the role of PARP-1 against UV-induced DNA damage. PARP-1 influences ~3.5% of the total transcriptome of embryonic liver and stem cells and regulates ~60-70% of genes controlling cell metabolism, cell cycle and transcription. Further, over-expression of PARP-1 and telomeric repeat binding factor-1 were also associated with age dependent telomere shortening in 'Duchenne muscular dystrophy'. PARP-1's role in neuronal BER indicates that it may influence age-related memory deficits and dementia. Progressive DNA damage and decreased PARP-1 activity in aging neurons eventually leads to programmed neuronal death and loss of memory consolidation. Apart from its role in repairing DNA damage, PARP-1 also plays important roles in transcription, cardiac remodeling, vasoconstriction, regulation of astrocyte and microglial function, long term memory and aging. Many additional functions of PARP-1 have now been demonstrated in biochemical and molecular signaling. Interestingly, over-expression of PARP-1 or DNA binding domain of PARP-1 (lacking catalytic domain) decreased DSB repair, indicating that its enzymatic activity is not essential in all repair processes. Initially identified as an enzyme that performs central roles in the repair of damaged DNA, PARP-1 participates in initiating base excision repair (BER) (PARP-1 -/- cells have impaired BER activity), nucleotide excision repair, single strand base repair mediated by DNA ligase III, XRCC1, poly nucleotide kinase, proliferating cell nuclear antigen and flap endonuclease-1, and contributes to double strand base (DSB) repair in an alternate non-homologous end joining pathway with DNA ligase III. PARP-1 is a nuclear protein with a wide range of physiological as well as pathological functions. The roles played by some of the PARP-1 fragments and their associated binding partners in the control of different forms of cell death are also discussed. This review focuses on specific suicidal proteases active towards PARP-1 to generate signature PARP-1 fragments that can identify key proteases and particular forms of cell death involved in pathophysiology. These PARP-1 signature fragments are recognized biomarkers for specific patterns of protease activity in unique cell death programs. PARP-1 is also a preferred substrate for several 'suicidal' proteases and the proteolytic action of suicidal proteases (caspases, calpains, cathepsins, granzymes and matrix metalloproteinases (MMPs)) on PARP-1 produces several specific proteolytic cleavage fragments with different molecular weights. In the CNS, PARP inhibition attenuates injury in pathologies like cerebral ischemia, trauma and excitotoxicity demonstrating a central role of PARP-1 in these pathologies. Recently, it has become widely appreciated that PARP-1 also participates in diverse physiological and pathological functions from cell survival to several forms of cell death and has been implicated in gene transcription, immune responses, inflammation, learning, memory, synaptic functions, angiogenesis and aging. The normal function of poly (ADP-ribose) polymerase-1 (PARP-1) is the routine repair of DNA damage by adding poly (ADP ribose) polymers in response to a variety of cellular stresses.
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