RMI2

RMI2 (BLAP18) is an OB-fold-containing scaffold subunit of the conserved BLM-Topoisomerase IIIα-RMI1-RMI2 (BTRR/dissolvasome) complex that governs the resolution of recombination and replication intermediates to enforce genome stability (PMID:18923083). The majority of cellular RMI2 exists in complex with Topo IIIα and RMI1, and its depletion destabilizes the complex, abolishes chromatin targeting of BLM, prevents BLM focus assembly under replication stress, and reduces double Holliday junction dissolution (PMID:18923083). Within the reconstituted complex RMI2 acts together with RMI1 to potentiate Topo IIIα-driven stimulation of BLM, conferring processivity on BLM-mediated 5′ DNA end resection (PMID:25200081), and the Topo IIIα-RMI1-RMI2 (TRR) subcomplex orients BLM to favor D-loop disruption over stabilization, providing quality control over the homologous recombination pathway toward non-crossover outcomes (PMID:35115525). Single-molecule analyses show TRR forms an open ssDNA gate whose mechanical size is modulated by dsDNA binding and by BLM, and that TRR processively relaxes highly negatively supercoiled DNA while remaining stably bound, supplying a mechanistic basis for resolving ultrafine anaphase bridges (PMID:35102151, PMID:41576078). Consistent with these biochemical roles, loss of RMI2 in human cells elevates sister chromatid exchange and produces anaphase DNA bridges and micronuclei, with impaired BLM and FANCD2 localization to ultrafine bridges (PMID:27977684). Separately from its dissolvasome function, MPS1 kinase phosphorylates RMI2 at serine 112 upon spindle assembly checkpoint activation, redirecting the complex between nucleoplasm and nuclear matrix to maintain mitotic arrest and prevent chromosomal instability, independent of BLM and of complex stability (PMID:24108125).

1. 2008 High

   Established RMI2 as an essential structural subunit of the BLM dissolvasome, answering whether the newly identified OB-fold protein had a defined role in the complex.

   Evidence Co-IP, siRNA depletion, chromatin fractionation, and in vitro dHJ dissolution assay in human cells

   PMID:18923083

   Open questions at the time

   • Did not resolve which contacts within the complex RMI2 mediates
   • Quantitative contribution of RMI2 to dissolution versus chromatin targeting not separated
2. 2013 High

   Defined a biochemical role for RMI2 beyond complex integrity, showing it potentiates BLM unwinding and resection processivity rather than merely scaffolding.

   Evidence In vitro reconstitution with purified human proteins and DNA unwinding/resection assays

   PMID:25200081

   Open questions at the time

   • Single lab
   • Did not isolate RMI2-specific contribution from RMI1 within the RMI1-RMI2 pair
3. 2013 Medium

   Uncovered a mitosis-specific, dissolvasome-independent function for RMI2 as an MPS1 phosphorylation substrate maintaining the spindle assembly checkpoint.

   Evidence Phospho-specific analysis, S112A mutagenesis, reciprocal Co-IP, and cellular phenotype assays

   PMID:24108125

   Open questions at the time

   • Mechanism of nucleoplasm/nuclear-matrix redistribution unresolved
   • Direct MPS1-RMI2 kinase-substrate relationship in vitro not fully reconstituted
4. 2016 High

   Confirmed the physiological requirement for RMI2 in genome maintenance using human null models, linking biochemistry to cellular phenotypes at replication intermediates.

   Evidence Patient-derived and CRISPR RMI2-knockout cells, sister chromatid exchange assays, immunofluorescence

   PMID:27977684

   Open questions at the time

   • Whether RMI2 loss phenotypes are fully accounted for by BLM mislocalization not established
   • No structural basis for ultrafine-bridge localization defect
5. 2021 Medium

   Extended RMI2 function to meiosis via its ortholog, showing conserved BTR-complex interdependence and roles in crossover control.

   Evidence C. elegans rmif-2 genetics, immunofluorescence, and mutant epistasis with HIM-6/BLM, TOP-3, RMH-1

   PMID:34252074

   Open questions at the time

   • Ortholog-based; human meiotic role not directly tested
   • Molecular basis of mutual localization dependence not defined
6. 2022 High

   Provided a mechanistic basis for how the complex enforces non-crossover recombination by reorienting BLM activity and defining the topoisomerase gate.

   Evidence Single-molecule FRET, optical tweezers, and D-loop disruption assays with purified TRR and BLM

   PMID:35102151 PMID:35115525

   Open questions at the time

   • RMI2-specific contribution to gate plasticity versus Topo IIIα/RMI1 not isolated
   • Structural model of the gate in its active state not resolved
7. 2025 Medium

   Expanded the dissolvasome interaction network, identifying RAD54L2 as a BTRR-proximal factor aiding BLM recruitment and non-crossover recombination.

   Evidence BioID proximity proteomics of BTRR, Co-IP, SCE assays, and ATPase-dead RAD54L2 mutant

   PMID:39870965

   Open questions at the time

   • Finding centers on RAD54L2; direct RMI2-RAD54L2 contact not shown
   • Whether RAD54L2 acts through RMI2 specifically is unknown
8. 2026 High

   Demonstrated processive supercoil relaxation and stable DNA retention by TRR, linking the topoisomerase mechanism to ultrafine anaphase bridge resolution.

   Evidence Single-molecule optical tweezers with fluorescence imaging and real-time supercoiling measurement

   PMID:41576078

   Open questions at the time

   • RMI2-specific role in processivity not dissected from the complex
   • In-cell relevance to UFB resolution inferred, not directly observed

• How RMI2's two roles — dissolvasome scaffolding and MPS1-dependent checkpoint maintenance — are coordinated, and the structural basis of its specific contacts within the complex, remain unresolved.
• No structure isolating RMI2 interfaces within BTRR
• Coupling between mitotic phosphorylation and dissolvasome function undefined