ADPRHL1 is a catalytically inactive member of the ADP-ribosylhydrolase family whose principal characterized role is in cardiac myofibrillogenesis and ventricular chamber outgrowth PMID:27217161. Although it lacks the active-site residues required for ADP-ribosylhydrolase catalysis, its function depends not on catalysis but on a modified substrate-binding cleft centered on a di-arginine (Arg271-Arg272) loop; disruption of this loop abolishes ventricular myofibril assembly, and cardiac activity is concentrated in the C-terminal portion of the protein [PMID:27217161, PMID:32726316]. Consistent with a direct structural role, recombinant ADPRHL1 localizes to stripes adjacent to the Z-disc and modulates actin filament and Z-disc dynamics, with both loss and overexpression disrupting sarcomere organization PMID:27217161. In human stem cell-derived cardiomyocytes, ADPRHL1 maintains focal adhesion formation, calcium transients, and electrophysiological activity by suppressing the ROCK-myosin II pathway, and pharmacological ROCK or myosin II inhibition rescues these defects PMID:37880701. Beyond the heart, wild-type ADPRHL1 restrains cell proliferation, while a recurrent germline loss-of-function variant (p.D78V) activates PARP1 and enhances DNA damage response and prostate cancer cell survival in a manner reversible by olaparib PMID:35816343. Its promoter is subject to epigenetic repression through an HDAC4/MEF2/SUV39H1 axis in cardiomyocytes PMID:34492228.
Recorded for reference. The AIGR evaluation found this grounding is coarse (collapses to general parents) and can contradict the narrative — do not import these GO ids directly; re-ground from the narrative + PMIDs.
| Year | Confidence | Finding | PMIDs | Journal |
|---|---|---|---|---|
| 2016 | High | Adprhl1 is essential for striated myofibril assembly and ventricular chamber outgrowth in Xenopus laevis; morpholino knockdown inhibits myofibrillogenesis while overexpression causes disarrayed, branching myofibrils with sarcomere division at the actin-Z-disc boundary, and recombinant Adprhl1 localizes to stripes adjacent to the Z-disc, indicating a direct role in modifying Z-disc and actin dynamics. | PMID:27217161 | Developmental biology |
| 2016 | Medium | Structural modelling indicates Adprhl1 is a pseudoenzyme lacking key catalytic residues required for ADP-ribosylhydrolase activity, classifying it as catalytically inactive despite belonging to the ADP-ribosylhydrolase protein family. | PMID:27217161 | Developmental biology |
| 2020 | High | CRISPR/Cas9 knockout targeting a di-arginine (Arg271-Arg272) peptide loop at the centre of the ancestral ADP-ribosylhydrolase binding cleft in exon 6 causes loss of ventricular myofibril assembly, demonstrating that the modified substrate-binding cleft—not catalytic activity—is required for Adprhl1 cardiac function; mice lacking exons 3-4 are normal but retain the smaller ADPRHL1 species, indicating cardiac activity is concentrated in the C-terminal protein portion. | PMID:32726316 | PloS one |
| 2023 | High | ADPRHL1 knockout in human embryonic stem cell-derived cardiomyocytes causes abnormal cell adhesion, disrupted focal adhesion formation, and perturbations in calcium transients and electrophysiological activity via excessive upregulation of the ROCK-myosin II pathway; pharmacological inhibition of ROCK or myosin II restores focal adhesions and improves electrical conduction and calcium activity. | PMID:37880701 | Stem cell research & therapy |
| 2022 | Medium | A recurrent ADPRHL1 germline loss-of-function mutation (c.A233T; p.D78V) activates PARP1, leading to increased H2O2- or cisplatin-induced DNA damage response and enhanced prostate cancer cell survival; wild-type ADPRHL1 expressed in prostate cancer cells suppresses cell proliferation and oncogenesis, and PARP1 inhibition with olaparib suppresses cell survival induced by mutant ADPRHL1. | PMID:35816343 | Molecular cancer research : MCR |
| 2021 | Medium | HDAC4 represses transcription from the Adprhl1 promoter through a mechanism requiring the methyltransferase SUV39H1; MEF2 binding sites are overrepresented in Adprhl1 promoter regions that gain activating histone marks (H3K9ac, H3K4me3) upon HDAC4 deletion, identifying the Adprhl1 promoter as a target of HDAC4/MEF2/SUV39H1-mediated epigenetic repression in cardiomyocytes. | PMID:34492228 | Journal of molecular and cellular cardiology |
| 2025 | Low | ARH2 (ADPRHL1) promotes M2 macrophage polarization and suppresses immune responses in lung adenocarcinoma by regulating the FPR2/PI3K/AKT signaling pathway; siRNA-mediated knockdown of ARH2 delivered via a nanoparticle system activates anti-tumor immune responses. | PMID:40801020 | Bioactive materials |