MacroD2

MACROD2, or macrodomain-containing protein 2, is a human gene that encodes a mono-ADP-ribosylhydrolase involved in reversing mono-ADP-ribosylation of proteins. It is part of the MACROD family, which also includes MACROD1 and MACROD3. The encoded protein contains a macrodomain that recognizes and binds mono-ADP-ribose and catalyzes its removal from substrates, thereby counteracting the activity of ADP-ribosyltransferases.

Biological role and mechanism: Mono-ADP-ribosylation is a reversible post-translational modification implicated in DNA repair, transcription, chromatin remodeling, and signaling. By hydrolyzing mono-ADP-ribose, MACROD2 modulates the level and duration of MARylation on target proteins, which can influence chromatin state and cellular responses to stress or DNA damage. This activity places MACROD2 within the broader ADP-ribosylation pathway alongside PARP family enzymes.

Localization and expression: MACROD2 transcripts are detected in multiple human tissues, and the protein has been described in cellular fractions compatible with nuclear functions, with some contexts reporting cytoplasmic presence as well. These patterns are consistent with proposed roles in chromatin regulation and gene expression.

Clinical relevance: Genetic alterations in the MACROD2 region have been reported in association with neurodevelopmental disorders, including autism spectrum disorders and intellectual disability, as well as in various cancers. In such cases, MACROD2 alterations may contribute to disease susceptibility, though their exact causal role is still under investigation and may involve neighboring genes or broader genomic context.

Related genes: MACROD2 is part of a family that includes MACROD1 and MACROD3, which share similar enzymatic activity and domain architecture.