| 2013 |
Mouse RNF212 is essential for meiotic crossing-over; it functions to couple chromosome synapsis to the formation of crossover-specific recombination complexes. RNF212 selectively localizes to a subset of recombination sites (an early step in crossover designation) and acts to stabilize meiosis-specific recombination factors including the MutSγ complex (MSH4-MSH5). Haploinsufficiency demonstrates that RNF212 is a dosage-sensitive, limiting factor for crossover control. |
Mouse knockout and heterozygous loss-of-function combined with immunofluorescence localization of recombination factors on meiotic chromosome spreads |
Nature genetics |
High |
23396135
|
| 2017 |
RNF212 acts as a SUMO E3 ligase on meiotic chromosome axes; RNF212-dependent SUMO conjugation establishes a checkpoint-like state that stalls recombination by rendering turnover of a subset of recombination factors dependent on HEI10-mediated ubiquitylation. Interdependent localization of SUMO, ubiquitin, and proteasomes along chromosome axes is mediated largely by RNF212 and HEI10. This SUMO–ubiquitin relay recruits proteasomes to chromosome axes to regulate meiotic recombination. |
Mouse genetics (Rnf212 KO and Hei10 mutants), immunofluorescence, SUMO/ubiquitin conjugation assays on meiotic spreads, proteasome recruitment to chromosomes |
Science (New York, N.Y.) |
High |
28059716
|
| 2014 |
RNF212 marks pre-crossover intermediates and its prolonged association with recombination sites (along with MutSγ) is a defining feature of the pre-CO state; CNTD1 is required for the transition from pre-CO to mature CO by regulating the association between HEI10 and RNF212 and CO machinery components. Loss of CNTD1 leads to failure to localize MutLγ and HEI10 at designated CO sites and to sustained high levels of MutSγ/RNF212 foci. |
Mouse Cntd1 knockout, immunofluorescence quantification of RNF212, MutSγ, HEI10, MutLγ foci on meiotic chromosome spreads |
The Journal of cell biology |
High |
24891606
|
| 2018 |
RNF212 also mediates oocyte quality control: it sensitizes oocytes to DSB-induced apoptosis within a narrow window as chromosomes desynapse. RNF212 is required for HORMAD1 (a negative regulator of inter-sister recombination) to associate with desynapsing chromosomes, and RNF212 impedes DSB repair, retaining a 'memory' of meiotic defects for quality control. |
Mouse Rnf212 knockout, oocyte survival assays, immunofluorescence for HORMAD1 on desynapsing chromosomes, DNA damage marker analysis |
Molecular cell |
High |
30270110
|
| 2025 |
RNF212, HEI10, and RNF212B are three distinct mammalian crossover-regulating (COR) RING-domain proteins with divergent spatiotemporal localization dynamics along synapsed chromosomes (including profound differences between spermatocytes and oocytes). Contrasting mutant phenotypes and genetic requirements indicate they play distinct but interdependent functions in regulating meiotic recombination, integrating signals from DNA breaks, homolog synapsis, cell cycle, and incipient crossover sites. |
Mouse genetics (single and double mutants), live imaging and immunofluorescence tracking of RNF212, HEI10, RNF212B localization dynamics in spermatocytes and oocytes |
Proceedings of the National Academy of Sciences of the United States of America |
High |
39761402
|
| 2024 |
RNF212B colocalizes and physically interacts with RNF212, forming foci along chromosomes from zygonema onward in a synapsis-dependent, DSB-independent manner. RNF212B foci formation depends genetically on Rnf212 but not on Msh4, Hei10, or Cntd1; unloading of RNF212B at end of pachynema depends on Hei10 and Cntd1. SUMOylome analysis and pull-down assays indicate RNF212B has ubiquitin E3 ligase activity. Double mutants for Rnf212b and Rnf212 are phenotypically identical to Rnf212b single mutants, while double heterozygotes show dosage-dependent CO reduction, indicating functional interplay between paralogs. |
Mouse knockouts (single and double), co-immunoprecipitation/pull-down, SUMOylome mass spectrometry, immunofluorescence on meiotic spreads, genetic epistasis |
Proceedings of the National Academy of Sciences of the United States of America |
High |
38865271
|
| 2025 |
HEIP1 directly interacts with HEI10 and orchestrates the recruitment of pro-CO E3 ligases RNF212 and RNF212B (as well as MutSγ complex) to meiotic recombination sites. Loss of HEIP1 impairs RNF212 and RNF212B localization at crossover sites, and recruitment of MutLγ resolution complex. |
Mouse Heip1 knockout, co-immunoprecipitation (HEIP1–HEI10 interaction), immunofluorescence for RNF212, RNF212B, HEI10, MutLγ on meiotic spreads |
Proceedings of the National Academy of Sciences of the United States of America |
High |
41118211
|
| 2019 |
Homozygous loss-of-function variants in human RNF212 cause meiotic arrest in males, establishing RNF212 as required for human male meiosis. Meiotic studies of testicular biopsies from mutation carriers confirmed functional consequences consistent with roles defined in mouse knockout models. |
Next-generation sequencing (gene panel), immunohistochemistry and immunocytochemistry on human testicular biopsies from homozygous RNF212 variant carriers |
Human reproduction (Oxford, England) |
Medium |
31125047
|
| 2014 |
An ENU-induced nonsense mutation in mouse Rnf212 (repro57 allele) causes male infertility with spermatocyte degeneration at late meiotic prophase, greatly reduced MLH1 (crossover) foci, absent chiasmata, and premature XY dissociation, confirming that RNF212 is required for crossover formation and late prophase progression. |
ENU mutagenesis screen, histology, MLH1 immunofluorescence on meiotic spreads, genetic mapping of repro57 mutation to Rnf212 |
Reproduction (Cambridge, England) |
Medium |
25342176
|
| 2024 |
Female repro57 (Rnf212 nonsense mutation) homozygous mutant oocytes exhibit complete aneuploidy with increased kinetochore distances, and derived embryos show significantly reduced morula/blastocyst rates with frequent cytokinesis failure and vacuole formation, indicating that RNF212 loss leads to premature sister chromatid separation that propagates through embryo development. |
In vitro fertilization of repro57 homozygous mutant oocytes, chromosome spreading and FISH for aneuploidy, immunofluorescence for kinetochore markers, embryo developmental tracking |
Reproduction (Cambridge, England) |
Medium |
39042717
|
| 2016 |
In C. elegans, the MAP kinase pathway (via MPK-1) coordinates crossover designation with SC protein disassembly; inactivation of MPK-1 at late pachytene is required for SC disassembly from long arms and depends on ZHP-3 (the C. elegans ortholog of RNF212/Zip3) and COSA-1 (CNTD1 ortholog), placing ZHP-3/RNF212 as a required factor downstream of crossover designation for coordinating SC remodeling. |
C. elegans genetics (ZHP-3/COSA-1 mutants), phosphorylation analysis of SYP-2, MAP kinase pathway manipulation by constitutively active and dominant-negative alleles |
eLife |
Medium |
26920220
|
| 2017 |
In budding yeast, Zip3 (the RNF212/ZHP-3 ortholog) recruits proteolytic core and regulatory proteasome particles to meiotic chromosomes (together with SC protein Zip1), and proteasome function is required for the coordinated transition entailing SC assembly and stable strand exchange of crossover-designated DSBs, establishing a conserved chromosome-axis-based proteasome recruitment role for this protein family. |
Yeast genetics, proteasome localization by immunofluorescence, Zip3 mutant analysis for chromosome pairing and crossover formation |
Science (New York, N.Y.) |
Medium |
28059715
|
| 2014 |
In yeast, Zip3 (RNF212 ortholog) promotes biased cutting of double Holliday junction intermediates toward crossover outcomes, as inferred from genome-wide recombination intermediate signatures in zip3 mutants compared to other ZMM mutants. |
Genome-wide sequencing of recombination products in yeast mutants (zip3, sgs1, mms4-md) to analyze conversion tracts and crossover/non-crossover signatures |
PLoS genetics |
Medium |
25329811
|
| 2018 |
In C. elegans, ZHP-4 (an RNF212-like paralog of ZHP-3) cooperates with ZHP-3 to enforce crossover formation at two distinct steps: formation of early joint molecules and transition of late CO intermediates into chiasmata. RING domain mutants show that ZHP-4 is required for localization of both ZHP-3 and ZHP-4 to the synaptonemal complex, and for stabilizing pro-CO factors (MSH-5, RMH-1, COSA-1) at designated CO sites. |
C. elegans genetics (zhp-4 null and hypomorphic mutants, RING domain mutants), immunofluorescence for pro-CO factors on meiotic chromosomes |
PLoS genetics |
Medium |
30379819
|