ZMYM4

ZMYM4 (ZNF262/KIAA0425) is a MYM-type zinc-finger protein whose tandem MYM zinc-binding motifs constitute the defining architectural feature of the MYM protein family (PMID:10486218). These MYM-type zinc fingers function as SUMO-interacting motifs (SIMs) that engage SUMO-2 through the same surface recognized by the canonical SIM consensus, placing ZMYM4 within SUMO-dependent protein interaction networks (PMID:25133527). Consistent with this, ZMYM4 is itself highly SUMOylated and was identified as a binding partner of the transcription factor B-MYB, an interaction that is stimulated upon induction of DNA damage (PMID:32439918). Knockdown of ZMYM4 in HEK293 cells produced no overt cell-cycle phenotype, and beyond its SUMO-interaction capacity and DNA-damage-stimulated B-MYB association, the precise molecular role of ZMYM4 in transcriptional regulation or the DNA-damage response has not been resolved in the available corpus (PMID:32439918).

1. 1999 Medium

   Established ZMYM4 as a distinct gene product and defined its core domain architecture, providing the structural framework for all later functional hypotheses.

   Evidence cDNA cloning, FISH chromosomal mapping, and sequence analysis identifying tandem MYM zinc-binding motifs

   PMID:10486218

   Open questions at the time

   • No biochemical or cellular function assigned to the protein or its MYM motifs
   • Zinc-binding and DNA/protein interaction inferred from sequence only
2. 2011 Low

   Traced the evolutionary origin of ZMYM4 and proposed that its DUF3504/MYM domain mediates protein-DNA or protein-protein interactions, framing a possible nucleic-acid-associated function.

   Evidence Phylogenetic, synteny, domain-architecture, and intron-position analysis (computational only)

   PMID:22011512

   Open questions at the time

   • Purely computational; no experimental test of DNA or protein binding by ZMYM4
   • Functional consequence of the DUF3504 domain in ZMYM4 not demonstrated
3. 2014 Low

   Assigned a biochemical activity to the MYM zinc fingers by showing they act as SUMO-interacting motifs binding SUMO-2, reframing MYM-family proteins as SUMO readers.

   Evidence SUMO-binding assays and domain truncation; direct binding shown for ZNF198/ZNF261, with ZMYM4/ZNF262 included as a homologous family member

   PMID:25133527

   Open questions at the time

   • Direct SUMO-2 binding was validated for paralogs, not for ZMYM4 itself
   • SUMO target and biological context of ZMYM4 SIM activity not defined
4. 2020 Medium

   Connected ZMYM4 to a specific cellular context by identifying it as a SUMOylated B-MYB interactor whose binding is induced by DNA damage, linking its SUMO-related properties to a transcription factor and a stress signal.

   Evidence AP-MS discovery with Co-IP confirmation, SUMOylation analysis, knockdown, and cell-cycle analysis in HEK293 cells

   PMID:32439918

   Open questions at the time

   • Functional consequence of the ZMYM4-B-MYB interaction unresolved (no cell-cycle effect on knockdown)
   • Whether ZMYM4 SUMOylation or SIM activity drives the DNA-damage-stimulated binding not established
   • Downstream transcriptional or repair outputs not identified

• The precise molecular function of ZMYM4 — whether it acts as a SUMO-dependent scaffold, transcriptional cofactor, or DNA-damage-response component — remains undefined.
• No demonstrated catalytic activity or defined substrate
• No structural model of MYM-domain engagement with SUMO or B-MYB
• Biological pathway and phenotype of ZMYM4 loss largely uncharacterized