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Recent developments indicate that macrodomains, an ancient and diverse protein domain family, are key players in the recognition, interpretation, and turnover of ADP-ribose (ADPr) signaling. Crucial to this is the ability of macrodomains to recognize ADPr either directly, in the form of a metabolic derivative, or as a modification covalently bound to proteins. Thus, macrodomains regulate a wide variety of cellular and organismal processes, including DNA damage repair, signal transduction, and immune response. Their importance is further indicated by the fact that dysregulation or mutation of a macrodomain is associated with several diseases, including cancer, developmental defects, and neurodegeneration. In this review, we summarize the current insights into macrodomain evolution and how this evolution influenced their structural and functional diversification. We highlight some aspects of macrodomain roles in pathobiology as well as their emerging potential as therapeutic targets.

Original publication

DOI

10.1146/annurev-biochem-060815-014935

Type

Journal article

Journal

Annu Rev Biochem

Publication Date

02/06/2016

Volume

85

Pages

431 - 454

Keywords

ADP-ribose, NAD, PARG, PARP family, posttranslational modifications, Adenosine Diphosphate Ribose, Animals, DNA Damage, DNA Repair, Escherichia coli Proteins, Evolution, Molecular, Humans, Isoenzymes, Multigene Family, Neoplasms, Phylogeny, Poly(ADP-ribose) Polymerases, Protein Domains, Protein Processing, Post-Translational, Repressor Proteins, Signal Transduction, Structural Homology, Protein, Virus Diseases