Structural Domains of PARP1

The protein structure of PARP1 has been identified. It contains four functional domains: (1) DBD, (2) nuclear localization signal (NLS), (3) automodification domain (AMD), and (4) Catalytic domains (CD). Figure 12.1 shows the PARP1 structure domains. The DBD also known as zinc fingers restrains to DNA breaks. The NLS has the role of ensuring the PARP1 is localized in the nucleus and is the site of caspase-3 cleavage. The AMD is the site of ADP-ribose polymers addition to PARP [73].

Several forms of molecules have been recognized as PARP activators, including histones and metal ions. PARP1 can be activated by histone H1 and H3. On the other hand, Sirtuin1 (SIRT-1), a histone deacetylase enzyme, is responsible for regulation of PARP1 activity. Cell death mediated by AIF occurs whenever SIRT-1 is absent and PARP is deregulated. In addition, some metal ions such as magnesium and calcium, which play a role in OS, can activate PARP activity thus illustrating the relationship between OS and PARP activity [74, 75]. OS causes calcium influx into the cytoplasm from the environment and also from endoplasmic reticu-lum. Rising of calcium in the cytoplasm leads to calcium influx into mitochondria and nucleus, which causes disruption of normal metabolism and PARP activity [74]. PARP activity may be inhibited by many endogenous and exogenous inhibitors such as hypoxanthine (endogenous) and tetracycline derivatives (exogenous) [76, 77]. Phosphorylation of PARP1 by extracellular signal-regulated kinases 1/2 (ERK1, 2) is necessary for PARP activation following DNA damage [78]. In addition, PARP phosphorylation may be induced by DNA-dependent protein kinase (DNA-PK), which is a major protein involved in repairing DNA double-strand breaks [79]. PARP1 can recruit other repair enzymes that are essential for repairing DNA damage and preserve DNA integrity. It has been shown that lack of PARP1 can inhibit BER activity; furthermore, PARP2 actively participates in BER pathways [80, 81].

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