INO80B

INO80B (also called hIes2/Ies2 and PAPA-1) is an evolutionarily conserved regulatory subunit of the INO80 ATP-dependent chromatin-remodeling complex, residing in the catalytic core module alongside the Ino80 SNF2 ATPase, Ies6, Tip49a/Tip49b, and Arp5 (PMID:21303910). Mechanistically, INO80B is a potent activator of the intrinsic ATPase rate of the Ino80 SNF2 ATPase, acting on the enzyme's catalytic turnover rather than on nucleosome binding (PMID:24297934). It is also required for stable assembly of the Arp5-Ies6 module onto the catalytic core, and through this it couples ATP hydrolysis to productive nucleosome sliding—a coupling that can be restored by a bypass mutation in Arp5, indicating that INO80B and Arp5/Ies6 act synergistically (PMID:26306040, PMID:27257055). Cryo-EM structures show INO80B contacts the nucleosome acidic patch and uses this contact to discriminate substrates, being essential for canonical nucleosome sliding but dispensable for hexasome sliding (PMID:41775336). Consistent with a chromatin-remodeling role, loss of the Ies2 ortholog impairs DNA damage repair and the replication-stress response (PMID:19933844). Independently of the complex, INO80B localizes to the nucleolus via its lysine/histidine cluster and suppresses proliferation by inducing G1 arrest in a nucleolar-localization-dependent manner (PMID:15556297), and it binds IGFBP-2 in the nucleus to antagonize IGFBP-2-driven growth (PMID:19095771).

1. 2004 Medium

   Before its role in chromatin remodeling was known, the question was whether PAPA-1/INO80B had an autonomous cellular function; this established it as a nucleolar protein that restrains the cell cycle.

   Evidence Confocal imaging and inducible expression with deletion mutants in HeLa cells

   PMID:15556297

   Open questions at the time

   • Does not connect nucleolar growth suppression to the INO80 complex
   • Molecular targets of the G1 arrest not identified
2. 2008 Medium

   To find a functional partner explaining the growth suppression, an interaction screen identified IGFBP-2 as a nuclear binding partner that INO80B antagonizes.

   Evidence Yeast two-hybrid, Co-IP, GST pull-down, siRNA/overexpression proliferation assays in prostate cancer cells and IGFBP-2 KO MEFs

   PMID:19095771

   Open questions at the time

   • Mechanism by which binding antagonizes IGFBP-2 signaling unresolved
   • Relationship to nucleolar localization not established
3. 2008 Low

   An open question was whether Ies2 dosage matters for genome maintenance; heterozygous yeast diploids showed gene dosage affects DNA repair capacity.

   Evidence Transposon mutagenesis and DNA repair assays in haploid/diploid S. cerevisiae

   PMID:18211810

   Open questions at the time

   • Single genetic observation with limited mechanistic detail
   • No molecular link to remodeling activity
4. 2009 Medium

   It was unclear which cellular processes require Ies2 within INO80; deletion in fission yeast placed it in DNA damage repair, replication-stress response, and nucleotide metabolism.

   Evidence ies2 deletion and phenotypic analysis in S. pombe with complex purification

   PMID:19933844

   Open questions at the time

   • Does not define the biochemical contribution of Ies2 to the complex
   • Phenotypes not yet mapped to remodeling mechanism
5. 2011 High

   The architectural question of where INO80B sits in the human complex was answered by assigning it to the catalytic core module rather than the dispensable metazoan-specific module.

   Evidence Biochemical purification of hINO80 subassemblies, domain mapping, and ATP-dependent remodeling assays

   PMID:21303910

   Open questions at the time

   • Does not define INO80B's specific biochemical activity within the core
6. 2013 High

   Having placed INO80B in the core, the question became what it does there; reconstitution showed it directly activates the intrinsic catalytic rate of the Ino80 ATPase.

   Evidence Reconstitution of INO80 subcomplexes ± Ies2 with direct ATPase measurements

   PMID:24297934

   Open questions at the time

   • How activation translates to nucleosome movement not yet defined
   • Structural basis of ATPase stimulation unknown
7. 2016 High

   Two studies resolved how INO80B couples catalysis to remodeling: it is required for stable Arp5-Ies6 module assembly and links ATP hydrolysis to productive nucleosome sliding, bypassable by an Arp5 mutation.

   Evidence Yeast IES2 deletion with Co-IP and chromatin-association assays; recombinant minimal human INO80 core ± Ies2 with sliding/ATPase assays and Arp5 bypass mutagenesis

   PMID:26306040 PMID:27257055

   Open questions at the time

   • Atomic-level basis of the Ies2-Arp5/Ies6 synergy not visualized at this stage
8. 2023 Medium

   The question of INO80B's role in transcriptional output identified its participation in a miR-372 regulatory feedback loop tied to p53/p21 signaling.

   Evidence RNA-seq, siRNA knockdown of INO80 subunits including Ies2, miR-372 mimics, and luciferase reporter assays

   PMID:37445863

   Open questions at the time

   • Direct chromatin targets of the loop not mapped
   • Specific contribution of Ies2 versus other subunits not isolated
9. 2026 High

   The structural basis of INO80B's substrate selectivity was resolved: it contacts the nucleosome acidic patch to discriminate nucleosomes from hexasomes, being essential for nucleosome but not hexasome sliding.

   Evidence Cryo-EM of human INO80 on canonical, H2A.Z, and hexasome substrates with in vitro sliding assays

   PMID:41775336

   Open questions at the time

   • How acidic-patch sensing is communicated to the ATPase not fully detailed
   • In vivo consequence of hexasome-vs-nucleosome discrimination untested

• It remains unresolved how INO80B's complex-bound remodeling role mechanistically connects to its complex-independent nucleolar, IGFBP-2-antagonizing, and growth-suppressive functions.
• No experiment unifies the chromatin-remodeling and free-protein activities
• Whether nucleolar INO80B acts within or outside the complex is unknown