Mono-ADP-ribosylhydrolase 2 (MACROD2)

Mono-ADP-ribosylhydrolase 2 (MACROD2) is an enzyme that catalyzes the removal of mono-ADP-ribose modifications from target proteins, reversing the effect of mono-ADP-ribosylation, a post-translational modification involved in cellular processes such as DNA repair and signal transduction[1][2]. It contains a single hyphenated macrodomain structure with a deep ADP-ribose binding cleft, facilitating high specificity for mono-ADP-ribosylated substrates over poly-ADP-ribosylated ones and acting particularly on proteins mono-ADP-ribosylated by PARP family members such as PARP1 and PARP10[1][2][3]. MACROD2 is found in the nucleus and cytoplasm, and can shuttle between these compartments in response to DNA damage, participating in the DNA damage response in a manner regulated by ATM kinase signaling[3]. Functionally, MACROD2 is a caretaker tumor suppressor: loss or deletion of the MACROD2 gene, seen frequently (~30%) in colorectal cancer, leads to compromised PARP1 activity, impaired DNA repair, chromosome instability, and promotes tumorigenesis[4]. MACROD2 also modulates the WNT signaling pathway by reversing PARP10-mediated ADP-ribosylation on GSK3β, thereby influencing β-catenin degradation and transcriptional regulation relevant to cancer biology[4]. No drugs are currently known to clinically target MACROD2, but its enzymatic properties and structural features have been elucidated, providing a potential platform for future drug discovery efforts[2]. Its loss, particularly in cancer, may serve as a biomarker of chromosomal instability and tumor progression[4].

Other names

ADP-ribose glycohydrolase MACROD2C20orf133dJ631M13.5MACRO domain-containing protein 2O-acetyl-ADP-ribose deacetylase MACROD2[Protein ADP-ribosylaspartate] hydrolase MACROD2[Protein ADP-ribosylglutamate] hydrolase MACROD2MACRO domain containing 2

Hydrolysis (removal) of mono-ADP-ribose from target proteins; Regulation of PARP1 (poly-ADP-ribose polymerase 1) activity