ADP-ribosylation is a protein modification synthesized from NAD+ by ADP-ribosyltransferases, of which there are 17 human enzymes, that use NAD+ as a cofactor to transfer a single ADP-ribose subunit (mono-ADP-ribosylation), or multiple subunits (poly-ADP-ribosylation), covalently to amino acid acceptor sites. In addition, mono-ADP-ribosylation can also be added by other enzymes, such as sirtuins or bacterial toxins. Poly(ADP-ribose) Glycohydrolases (PARG) degrade the modification, making ADP-ribose a dynamic and reversible modification. ADP-ribosylation has numerous and diverse effects on protein function and cellular pathways. The modification has been found to affect protein stability and activity, as well as serve as a scaffold to recruit other protein factors. ADP-ribosylation is involved in DNA damage, transcription, chromatin organization, stress responses, apoptosis, and telomere maintenance, just to name a few.
A multitude of techniques has been developed to identify ADP-ribosylated substrates. Some techniques use antibodies or protein domains that bind ADP-ribose to pull out the modification from cell lysates and use mass spectrometry to identify the proteins that come down. Other techniques utilize protein arrays and recombinant PARPs to identify specific substrates. Because of the diverse roles of ADP-ribosylation and ADP-ribosyltransferases play in the cell, ADP-ribosylation and PARP activity have been implicated in a handful of disease pathogenesis, such as cancer, neurological disease, and aging. Thus, understanding substrate specificity, site identification on substrates, and how protein function is affected by the modification are of utmost importance and have the potential to improve our understanding of the biology of disease. Click here to learn more about ADP-ribosylation.
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