RAD54L2

RAD54L2 (ARIP4) is a SNF2-family nuclear ATPase that operates at the interface of steroid-hormone transcription and genome integrity, coupling its ATP-driven activity to the resolution of topological and recombination intermediates on chromatin (PMID:19692572, PMID:38055822). It recognizes sumoylated nuclear receptors through SUMO-interacting motifs and a dedicated receptor-binding region, and its ATPase activity is stimulated by sumoylated Ad4BP/SF-1 together with cognate dsDNA; through transient promoter recruitment it modulates steroid receptor-dependent transcription, suppressing Ad4BP/SF-1-mediated transcription while synergizing with DYRK1A to enhance androgen- and glucocorticoid-receptor transactivation (PMID:15199138, PMID:19692572). At transcription start sites RAD54L2 co-occupies sites of paused RNA Pol II, directly binds and unwinds R-loops, and works with topoisomerase IIβ to permit transient DSB formation that releases paused polymerase upon androgen stimulation (PMID:39028815). Its ATPase activity recognizes sumoylated TOP2 and, in conjunction with ZATT/ZNF451 and independently of TDP2, promotes resolution of TOP2 cleavage complexes and turnover of TOP2 from chromatin, thereby limiting DSB exposure; accordingly, RAD54L2 loss sensitizes cells to TOP2 poisons (PMID:38055811, PMID:38055822). RAD54L2 also physically associates with BLM helicase and is required for its chromatin recruitment, suppressing sister chromatid exchanges and favoring non-crossover recombination in an ATPase-dependent manner (PMID:39870965). Additional contexts include a TRAF3-DYRK1A-RAD54L2 complex that maintains ACE2 expression and supports SARS-CoV-2 entry (PMID:38651897), and a direct interaction with the p62 UBA domain that links RAD54L2 protein levels to nutrient starvation (PMID:26412716).

1. 2004 Medium

   Established RAD54L2/ARIP4 as a nuclear partner of DYRK1A that functionally enhances steroid hormone receptor transcription, placing it in hormone-dependent gene regulation.

   Evidence Co-IP, colocalization imaging, transactivation reporters and RNAi in HEK293 cells and hippocampal neurons

   PMID:15199138

   Open questions at the time

   • No in vitro reconstitution of the DYRK1A interaction
   • Mechanism by which the pair enhances transactivation not defined
   • Single-lab finding
2. 2009 High

   Defined the molecular logic of RAD54L2 recruitment, showing it reads sumoylated nuclear receptors via SUMO-interacting motifs and that receptor plus DNA stimulate its ATPase, linking enzymatic activity to transcriptional repression.

   Evidence Affinity purification, Co-IP, ATPase assays, ChIP and siRNA on Ad4BP/SF-1 target promoters

   PMID:19692572

   Open questions at the time

   • Substrate of the ATPase on chromatin not identified
   • Reconciliation with the activating role seen with DYRK1A unresolved
3. 2015 Medium

   Revealed a post-translational control point, showing the autophagy receptor p62 directly binds RAD54L2 and governs its abundance under starvation.

   Evidence NMR mapping of the p62 UBA interaction, Co-IP, and protein-level measurements under nutrient starvation

   PMID:26412716

   Open questions at the time

   • Whether degradation is autophagic versus proteasomal not resolved
   • Functional consequence of RAD54L2 turnover for transcription/genome integrity untested
   • Single-lab finding
4. 2023 High

   Identified a genome-protective function: RAD54L2 recognizes sumoylated TOP2, drives ATPase-dependent resolution of TOP2 cleavage complexes via ZATT/ZNF451 and independently of TDP2, and promotes TOP2 turnover from chromatin, explaining TOP2-poison sensitivity upon its loss.

   Evidence Co-IP, chromatin fractionation, ATPase-mutant functional assays, TDP2 epistasis, and viability assays in RAD54L2 knockout/knockdown cells; two companion papers

   PMID:38055811 PMID:38055822

   Open questions at the time

   • Structural basis of sumoylated-TOP2 recognition not solved
   • How ATPase activity mechanically achieves TOP2cc resolution undefined
5. 2024 High

   Connected RAD54L2 to transcriptional pause release, showing it co-occupies TSSs with paused Pol II, unwinds R-loops directly, and cooperates with TOP2β to generate transient DSBs needed for androgen-stimulated polymerase release.

   Evidence ChIP-seq, Co-IP, R-loop immunofluorescence, siRNA, and in vitro R-loop unwinding reconstitution

   PMID:39028815

   Open questions at the time

   • How R-loop unwinding is coordinated with TOP2-dependent DSB formation unresolved
   • Generality beyond AR target genes not established
6. 2024 Medium

   Placed RAD54L2 in a TRAF3-DYRK1A-RAD54L2 complex that sustains ACE2 expression, identifying a host-factor role in SARS-CoV-2 entry.

   Evidence Genome-wide CRISPR knockout screen, Co-IP, RT-qPCR, and viral entry assays

   PMID:38651897

   Open questions at the time

   • Complex not reconstituted in vitro
   • Mechanism linking the complex to ACE2 transcription undefined
   • Single-lab finding
7. 2025 High

   Extended RAD54L2's recombination role, showing it recruits BLM helicase to chromatin and suppresses sister chromatid exchange in favor of non-crossover recombination, dependent on an intact ATPase domain.

   Evidence BioID proximity proteomics, Co-IP, chromatin fractionation, SCE assays, and ATPase-domain mutant analysis

   PMID:39870965

   Open questions at the time

   • Direct mechanism of BLM recruitment not defined
   • Relationship to its TOP2 and R-loop functions unintegrated

• How RAD54L2's roles in hormone-receptor transcription, R-loop/TOP2 processing, and BLM-dependent recombination are mechanistically unified by a single ATPase activity remains unresolved.
• No structural model of the enzyme or its substrate engagement
• Whether transcriptional and recombination functions are separable is unknown