Abstract
Poly(ADP-ribosyl)ation (PARylation) is an essential post-translational modification catalyzed by poly(ADP-ribose) polymerase (PARP) enzymes. Poly(ADP-ribose) polymerase 1 (PARP1) is a well-characterized member of the PARP family. PARP1 plays a crucial role in multiple biological processes and PARP1 activation contributes to the development of various inflammatory and malignant disorders, including lung inflammatory disorders, cardiovascular disease, ovarian cancer, breast cancer, and diabetes. In this review, we will focus on the role and molecular mechanisms of PARPs enzymes in inflammation- and metabolic-related diseases. Specifically, we discuss the molecular mechanisms and signaling pathways that PARP1 is associated with in the regulation of pathogenesis. Recently, increasing evidence suggests that PARP inhibition is a promising strategy for intervention of some diseases. Thus, our in-depth understanding of the mechanism of how PARPs are activated and how their signaling downstream effecters can provide more potential therapeutic targets for the treatment of the related diseases in the future is crucial.
Highlights
Poly(ADP-ribose) polymerases (PARPs), known as ADP-ribosyltransferases (ARTs), are a family of proteins that play key roles in various biological processes [1,2]
Poly(ADP-ribose) polymerase 1 (PARP1) is the prototypical and founding member of the PARP family, which can be divided into three functional domains: (1) the amino-terminal DNA-binding domain l (DBD) contains three zinc fingers, a nuclear localization signal (NLS), and a caspase-3 cleavage site; (2) the central automodification domain (AMD) contains numerous glutamic acid and aspartic acid residues, which is consistent with the fact that it is the main site of PARP1 automodification
This domain contains a breast cancer susceptibility gene1 C-terminus (BRCT) motif, a protein-protein interaction motif, which is commonly found in proteins involved in DNA repair and control of the cell cycle [15], the PARP1 BRCT domain is required for the interaction between PARP1 with several partner proteins, including X-ray repair cross complement gene 1(XRCC1) [16] and histones [17]
Summary
Poly(ADP-ribose) polymerases (PARPs), known as ADP-ribosyltransferases (ARTs), are a family of proteins that play key roles in various biological processes [1,2]. Except for a splice variant of PARP13, PARP13.2, all other PARP members contain a classical PARP domain, which catalyzes ADP-ribosylation of target proteins (Figure 1) Based on their domain schema, PARP superfamily members can be divided into four sub-families: (1) DNA-dependent PARPs, which are activated by discontinuous DNA structures via amino-terminal DNA-binding domains. PARP1 is the prototypical and founding member of the PARP family, which can be divided into three functional domains: (1) the amino-terminal DNA-binding domain l (DBD) contains three zinc fingers, a nuclear localization signal (NLS), and a caspase-3 cleavage site; (2) the central automodification domain (AMD) contains numerous glutamic acid and aspartic acid residues, which is consistent with the fact that it is the main site of PARP1 automodification This domain contains a breast cancer susceptibility gene C-terminus (BRCT) motif, a protein-protein interaction motif, which is commonly found in proteins involved in DNA repair and control of the cell cycle [15], the PARP1 BRCT domain is required for the interaction between PARP1 with several partner proteins, including X-ray repair cross complement gene 1(XRCC1) [16] and histones [17]. This article will focus on the important roles and molecular mechanisms of PARP1 in inflammationand metabolic-related diseases
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