Affinage

RNF212B

E3 ubiquitin-protein ligase RNF212B · UniProt A8MTL3

Length
300 aa
Mass
33.6 kDa
Annotated
2026-06-10
10 papers in source corpus 5 papers cited in narrative 6 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 5/6 claims corpus-supported (83%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

RNF212B is a meiosis-specific RING-domain E3 ubiquitin ligase essential for crossover designation and maturation during both male and female meiosis (PMID:38865271). It loads onto synapsed chromosomes from zygonema onward in a synapsis-dependent, DSB-independent manner, where it colocalizes and physically interacts with its paralog RNF212, and its foci then consolidate at maturing crossover sites together with HEI10, CNTD1, and MLH1 by late pachynema (PMID:38865271). Chromosomal loading of RNF212B depends genetically on Rnf212 but not on Msh4, Hei10, or Cntd1, while its removal at the end of pachynema requires Hei10 and Cntd1, placing RNF212B downstream of RNF212 yet under HEI10/CNTD1-dependent turnover (PMID:38865271); recruitment to crossover sites further requires HEIP1 (PMID:41118211, PMID:40909735). Functionally, RNF212B promotes retention of pro-crossover factors MSH4, TEX11, RPA, and MZIP2, and its loss eliminates late crossover intermediates (MLH1 foci), producing largely univalent chromosomes at diakinesis (PMID:38865271). RNF212B, RNF212, and HEI10 display divergent, sex-specific localization dynamics, indicating distinct but interdependent roles in integrating DNA-break, synapsis, and cell-cycle signals at incipient crossover sites (PMID:39761402). A homozygous nonsense mutation in RNF212B causes severe human male infertility with high sperm and embryo aneuploidy, and disruption of Drosophila orthologs reduces male fertility, establishing a conserved meiosis-specific requirement (PMID:37124137).

Mechanistic history

Synthesis pass · year-by-year structured walk · 5 steps
  1. 2023 Medium

    Established RNF212B as a meiosis-specific factor whose loss causes human infertility, defining its physiological importance before its molecular mechanism was known.

    Evidence Exome sequencing of an infertile male, scRNA-seq expression, FISH aneuploidy analysis, and Drosophila ortholog fertility assays

    PMID:37124137

    Open questions at the time
    • Single human family with one loss-of-function variant
    • Molecular activity of the protein not addressed
    • Conserved Drosophila role shown despite absence of male recombination, leaving the mechanistic basis unresolved
  2. 2024 High

    Defined RNF212B as a catalytically active RING-E3 ligase that interacts with RNF212 and marks maturing crossover sites, answering what the protein is and where it acts.

    Evidence Co-IP, immunofluorescence colocalization, knockout and catalytic-mutant mice, SUMOylome and pull-down assays

    PMID:38865271

    Open questions at the time
    • Physiological ubiquitination substrates at crossover sites not identified
    • Relationship between catalytic activity and SUMOylome changes not mechanistically resolved
    • Single lab
  3. 2024 High

    Ordered RNF212B within the crossover pathway by showing its loading depends on RNF212 and its unloading on HEI10/CNTD1, and that it sustains pro-crossover factor retention.

    Evidence Genetic epistasis across single and double mutant mice with immunofluorescence for MSH4, TEX11, RPA, MZIP2, and MLH1

    PMID:38865271

    Open questions at the time
    • Direct molecular basis of RNF212-dependent loading unknown
    • How RNF212B promotes retention of pro-CO factors mechanistically unclear
  4. 2025 High

    Resolved that RNF212B, RNF212, and HEI10 have distinct, sex-specific dynamics, establishing non-redundant yet interdependent roles in coordinating prophase-I events.

    Evidence Live and fixed immunofluorescence dynamics and mutant phenotype comparison across paralogs in spermatocytes and oocytes

    PMID:39761402

    Open questions at the time
    • Molecular drivers of the divergent spatiotemporal dynamics not identified
    • Basis of male-versus-female differences unexplained
  5. 2025 Medium

    Identified HEIP1 as an upstream determinant of RNF212B recruitment to maturing crossover sites.

    Evidence Heip1 knockout mice with immunofluorescence for RNF212B localization; HEIP1-HEI10 interaction by co-IP

    PMID:40909735 PMID:41118211

    Open questions at the time
    • Direct HEIP1-RNF212B physical interaction not demonstrated
    • Recruitment shown by IF in a single lab without biochemical reconstitution

Open questions

Synthesis pass · forward-looking unresolved questions
  • The physiological ubiquitination substrates of RNF212B and how its E3 activity mechanistically drives crossover maturation remain undefined.
  • No substrate identified for the RING-E3 activity
  • No structural model of RNF212B or its complexes
  • Mechanism linking ubiquitination to pro-CO factor retention unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0016740 transferase activity 1 GO:0140096 catalytic activity, acting on a protein 1
Localization
GO:0000228 nuclear chromosome 2
Pathway
R-HSA-1474165 Reproduction 3 R-HSA-1640170 Cell Cycle 1
Partners
CNTD1HEI10HEIP1MLH1RNF212

Evidence

Reading pass · 6 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2024 RNF212B is a RING-E3 ligase with ubiquitin activity that is essential for crossover designation and maturation during male and female meiosis in mice. RNF212B colocalizes and physically interacts with RNF212, forming foci along chromosomes from zygonema onward in a synapsis-dependent and DSB-independent manner. These foci consolidate into larger foci at maturing crossover sites, colocalizing with HEI10, CNTD1, and MLH1 by late pachynema. Co-immunoprecipitation, immunofluorescence/colocalization, mouse knockout, active-site mutagenesis (catalytically inactive RNF212B), SUMOylome analysis of testes, pull-down assay with SUMO- and Ubiquitin-tagged HeLa cells Proceedings of the National Academy of Sciences of the United States of America High 38865271
2024 RNF212B foci formation depends genetically on Rnf212 but not on Msh4, Hei10, or Cntd1. The unloading of RNF212B at the end of pachynema is dependent on Hei10 and Cntd1. Double mutants for Rnf212b and Rnf212 exhibit an identical phenotype to Rnf212b single mutants, while double heterozygotes show a dosage-dependent reduction in crossover number, indicating functional interplay between paralogs. Genetic epistasis analysis using single and double mutant mice (Rnf212b KO, Rnf212 KO, Msh4 KO, Hei10 KO, Cntd1 KO combinations); immunofluorescence Proceedings of the National Academy of Sciences of the United States of America High 38865271
2024 Loss of RNF212B reduces localization of pro-crossover factors MSH4, TEX11, RPA, and MZIP2, and eliminates late crossover intermediates (MLH1 foci), resulting in mostly univalent chromosomes at diakinesis due to loss of the majority of crossovers. Mouse knockout (Rnf212b null), immunofluorescence for pro-CO factors, diakinesis chromosome spreads Proceedings of the National Academy of Sciences of the United States of America High 38865271
2025 RNF212B, RNF212, and HEI10 show divergent spatiotemporal localization dynamics along synapsed chromosomes, with profound differences between spermatocytes and oocytes. Contrasting mutant phenotypes and genetic requirements establish that RNF212B plays distinct but interdependent functions from RNF212 and HEI10 in regulating meiotic recombination and coordinating meiotic prophase-I events by integrating signals from DNA breaks, homolog synapsis, the cell-cycle, and incipient crossover sites. Live and fixed immunofluorescence localization dynamics, mouse mutant phenotype comparison, genetic epistasis Proceedings of the National Academy of Sciences of the United States of America High 39761402
2025 HEIP1 promotes the recruitment of RNF212B (along with HEI10, RNF212, and MutSγ) to maturing crossover sites. RNF212B recruitment is thus dependent on HEIP1 function during meiotic prophase I. Mouse Heip1 knockout with immunofluorescence for RNF212B localization; direct interaction of HEIP1 with HEI10 shown by co-immunoprecipitation Proceedings of the National Academy of Sciences of the United States of America Medium 40909735 41118211
2023 A homozygous nonsense mutation in RNF212B causes severe male infertility with high aneuploidy rates in sperm and IVF embryos. RNF212B shows meiosis-specific expression by scRNA-seq. Inactivation of Drosophila RNF212B orthologs significantly reduces male fertility, indicating a conserved role in spermatogenesis beyond meiotic recombination (since male Drosophila lack recombination). Exome sequencing, scRNA-seq, FISH aneuploidy analysis of sperm and embryos, Drosophila ortholog RNAi/knockout male fertility assay HGG advances Medium 37124137

Source papers

Stage 0 corpus · 10 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2016 Conserved Genetic Architecture Underlying Individual Recombination Rate Variation in a Wild Population of Soay Sheep (Ovis aries). Genetics 126 27029733
2018 A Genomic Region Containing REC8 and RNF212B Is Associated with Individual Recombination Rate Variation in a Wild Population of Red Deer (Cervus elaphus). G3 (Bethesda, Md.) 37 29764960
2024 RNF212B E3 ligase is essential for crossover designation and maturation during male and female meiosis in the mouse. Proceedings of the National Academy of Sciences of the United States of America 18 38865271
2025 Distinct and interdependent functions of three RING proteins regulate recombination during mammalian meiosis. Proceedings of the National Academy of Sciences of the United States of America 12 39761402
2023 A pathogenic variant in the uncharacterized RNF212B gene results in severe aneuploidy male infertility and repeated IVF failure. HGG advances 8 37124137
2025 Genomic and chromosomal architectures underlying fertility maintenance in the testes of intergeneric homoploid hybrids. Science China. Life sciences 1 40426007
2025 A variant in RNF212B may contribute to female infertility and recurrent pregnancy loss. HGG advances 0 40259604
2025 An Increase in Male Recombination Rate With Age in Dairy Cattle Is Heritable and Polygenic. Journal of animal breeding and genetics = Zeitschrift fur Tierzuchtung und Zuchtungsbiologie 0 40515540
2025 HEIP1 orchestrates pro-crossover protein activity during mammalian meiosis. bioRxiv : the preprint server for biology 0 40909735
2025 HEIP1 orchestrates pro-crossover protein activity during mammalian meiosis. Proceedings of the National Academy of Sciences of the United States of America 0 41118211

Missed literature

Know a paper Affinage missed for RNF212B? Flag it for the maintainers and the community.

No submissions yet.