PARP-1 cleavage fragments: signatures of cell-death proteases in neurodegeneration
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REVIEW
Open Access
PARP-1 cleavage fragments: signatures of cell-death proteases in neurodegeneration Ganta Vijay Chaitanya1,2, Alexander J Steven2, Phanithi Prakash Babu1*
Abstract 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. 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. 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. 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. These PARP-1 signature fragments are recognized biomarkers for specific patterns of protease activity in unique cell death programs. 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. 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. Introduction PARP-1 is a nuclear protein with a wide range of physiological as well as pathological functions. 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) [1,2], 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 nonhomologous end joining pathway with DNA ligase III [3-6]. 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 [7]. Many additional functions of PARP-1 have now been demonstrated in biochemical and molecular signaling [8]. Apart from its role in repairing DNA damage, PARP-1 also plays important roles in transcription, cardiac * Correspondence: [email protected] 1 Department of Biotechnology, School of Life Sciences, University of Hyderabad, Hyderabad, India Full list of author information is available at the end of the article
remodeling, vasoconstriction, regulation of astrocyte and microglial function, long term memory and aging [9-17]. Progressive DNA damage and decreased PARP-1 activity in a
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