ACTR5

ACTR5 is a component of the INO80 chromatin remodeling complex that functions as a dependency for hepatocellular carcinoma proliferation (PMID:36563143). Its loss-of-function activates CDKN2A expression and ablates CDK/E2F-driven cell cycle signaling, thereby attenuating tumor growth (PMID:36563143). ACTR5 acts together with its partner IES6 through a mechanism distinct from the canonical INO80 complex, since high-density CRISPR tiling profiles of ACTR5 and IES6 diverge from those of other INO80 subunits (PMID:36563143). Beyond this chromatin-associated cell cycle role, no further biochemical mechanism (substrate specificity, recruitment, or structural basis of CDKN2A repression) has been characterized in the available corpus.

1. 2022 Medium

   Established ACTR5 as a functional tumor dependency by linking its loss to a defined molecular phenotype, answering whether this INO80 subunit has a non-redundant role in cancer cell proliferation.

   Evidence Epigenetics-focused CRISPR interference screen and gene tiling scans with cell cycle and tumor growth readouts in HCC

   PMID:36563143

   Open questions at the time

   • Direct molecular mechanism by which ACTR5 represses CDKN2A is not defined
   • Whether the dependency extends beyond HCC is untested
   • No biochemical demonstration of ACTR5 binding at the CDKN2A locus
2. 2022 Medium

   Distinguished ACTR5/IES6 function from the canonical INO80 complex, addressing whether ACTR5's pro-proliferative role depends on intact INO80.

   Evidence Differential high-density CRISPR tiling dependency profiling comparing ACTR5/IES6 against other INO80 subunits

   PMID:36563143

   Open questions at the time

   • Biochemical nature of the INO80-independent ACTR5/IES6 module is not characterized
   • Whether ACTR5/IES6 form a stable distinct complex is unresolved
3. 2025 Low

   Implicated ACTR5 as a positive regulator of type I interferon signaling, addressing a possible role outside cell cycle control via a disease-associated variant.

   Evidence IFN-β luciferase reporter assay using a patient-derived de novo ACTR5 variant

   PMID:40386946

   Open questions at the time

   • Single luciferase assay with one patient variant and no mechanistic follow-up
   • Connection between ACTR5's chromatin role and IFN signaling is undefined
   • No demonstration of endogenous ACTR5 acting in the IFN pathway

• How ACTR5 mechanistically represses CDKN2A and whether this connects to its reported interferon-regulatory activity remains unknown.
• No structural or biochemical model of ACTR5 action
• No identified DNA target or recruitment mechanism at CDKN2A
• Relationship between cell cycle and interferon roles unestablished