A role of intracellular mono-ADP-ribosylation in cancer biology.

During the development, progression and dissemination of neoplastic lesions, cancer cells can hijack normal pathways and mechanisms. This includes the control of the function of cellular proteins through reversible post-translational modifications, such as ADP-ribosylation, phosphorylation, and acetylation. In the case of mono-ADP-ribosylation and poly-ADP-ribosylation, the addition of one or several units of ADP-ribose to target proteins occurs via two families of enzymes that can generate ADP-ribosylated proteins: the diphtheria toxin-like ADP-ribosyltransferase (ARTD) family, comprising 17 different proteins that are either poly-ADP-ribosyltransferases or mono-ADP-ribosyltransferases or inactive enzymes; and the clostridial toxin-like ADP-ribosyltransferase family, with four human members, two of which are active mono-ADP-ribosyltransferases, and two of which are enzymatically inactive. In line with a central role for poly-ADP-ribose polymerase 1 in response to DNA damage, specific inhibitors of this enzyme have been developed as anticancer therapeutics and evaluated in several clinical trials. Recently, in combination with the discovery of a large number of enzymes that can catalyse mono-ADP-ribosylation, the role of this modification has been linked to human diseases, such as inflammation, diabetes, neurodegeneration, and cancer, thus revealing the need for the development of specific ARTD inhibitors. This will provide a better understanding of the roles of these enzymes in human physiology and pathology, so that they can be targeted in the future to generate new and efficacious drugs. This review summarizes our present knowledge of the ARTD enzymes that are involved in mono-ADP-ribosylation reactions and that have roles in cancer biology. In particular, the well-documented role of macro-containing ARTD8 in lymphoma and the putative role of ARTD15 in cancer are discussed.