| 2016 |
ZFC3H1 is a central component of the poly(A) tail exosome targeting (PAXT) connection, acting as a link between the RNA helicase hMTR4 and the nuclear poly(A)-binding protein PABPN1 to facilitate nuclear exosome degradation of polyadenylated transcripts. ZFC3H1/PABPN1 and ZCCHC8/RBM7 contact hMTR4 in a mutually exclusive manner, establishing that NEXT and PAXT are distinct, competing hMTR4-adaptor complexes targeting transcripts of different maturation status. |
Protein co-immunoprecipitation, depletion/knockdown with RNA-seq readout, identification of mutual exclusivity by interaction assays |
Molecular cell |
High |
27871484
|
| 2017 |
ZFC3H1 forms a distinct complex with MTR4 (separate from NEXT) that is required for nuclear surveillance of prematurely terminated RNAs (ptRNAs) and upstream antisense RNAs (uaRNAs). Knockdown of either Mtr4 or ZFC3H1 causes these lncRNAs to accumulate in the cytoplasm and associate with active ribosomes, leading to global repression of translation, establishing a role for the Mtr4/ZFC3H1 complex in preventing cytoplasmic transport and translational disruption. |
Complex purification/isolation, siRNA knockdown, cellular fractionation, polysome profiling, RNA immunoprecipitation |
Genes & development |
High |
28733371
|
| 2018 |
ZFC3H1 is required for the formation of distinct nuclear foci containing polyadenylated RNA when exosome function is abolished. In the absence of ZFC3H1, selected polyadenylated RNAs (coding and non-coding) are exported to the cytoplasm via the mRNA export factor AlyREF, establishing ZFC3H1 as a central nuclear pA+ RNA retention factor that counteracts nuclear export activity. |
Co-localization imaging (RNA FISH + immunofluorescence), siRNA knockdown, cellular fractionation, AlyREF epistasis experiments |
Cell reports |
High |
29768216
|
| 2018 |
ZFC3H1 physically associates with the HIV-1 TAR region and represses HIV-1 transcriptional output and RNAPII recruitment to the LTR. Knockdown of ZFC3H1 increases HIV-1 expression and reactivates HIV-1 from latently infected PBMCs. |
ChIP (chromatin immunoprecipitation), siRNA knockdown, reporter assays, flow cytometry of GFP-positive J-Lat cells, ex vivo PBMC infection |
PLoS pathogens |
Medium |
29554134
|
| 2019 |
NRDE2 inhibits ZFC3H1 interaction with MTR4 by binding MTR4 via a conserved MTR4-interacting domain (MID), locking MTR4 in a closed conformation and thereby blocking exosome recruitment. Structural and biochemical data confirm that NRDE2 competes with ZFC3H1 for binding to key residues on MTR4. |
Structural analysis, biochemical interaction assays, mutagenesis of MTR4-interacting domain, Co-IP |
Genes & development |
High |
30842217
|
| 2019 |
Knockout of ZFC3H1 in mouse embryonic stem cells impairs differentiation and leads to de-repression of PRC2-controlled developmental genes, paralleled by decreased PRC2 binding to chromatin, reduced H3K27 methylation, and compromised PRC2 complex stability due to elevated nonspecific RNA bound to PRC2 components. |
CRISPR/Cas9 knockout, ChIP-seq for H3K27me3 and PRC2, RNA-seq, RNA immunoprecipitation |
Cell reports |
High |
31722198
|
| 2019 |
Celastramycin binds ZFC3H1 as a direct binding partner (pulled down by celastramycin), and ZFC3H1 mediates celastramycin's effects on HIF-1α and NF-κB protein levels, reactive oxygen species, and mitochondrial metabolism in pulmonary artery smooth muscle cells. |
Affinity pull-down with celastramycin, siRNA knockdown, western blotting, functional cellular assays |
Circulation research |
Medium |
31195886
|
| 2020 |
ZFC3H1 functions as the core dimer partner of MTR4 in the PAXT connection, and three additional proteins—ZC3H3, RBM26, and RBM27—are required for PAXT function. ZC3H3 interacts directly with the MTR4-ZFC3H1 dimer, and loss of any newly identified component results in accumulation of PAXT substrates. |
Proteomics of nuclear pA+-RNA bound proteins, Co-IP of MTR4-ZFC3H1 complexes, siRNA knockdown with RNA-seq readout |
Nucleic acids research |
High |
31950173
|
| 2021 |
Upon exosome inactivation, ZFC3H1 forms nuclear condensates that prevent polyadenylated RNA trafficking to nuclear speckles, thereby blocking export competence. Systematic domain mapping revealed that ZFC3H1 uses distinct domains for condensation and for RNA degradation; condensation activity is required for nuclear RNA retention but not for RNA degradation. |
Live-cell imaging, domain deletion/mutation analysis, RNA FISH, siRNA knockdown, fluorescence microscopy of nuclear speckles |
Nucleic acids research |
Medium |
34530450
|
| 2022 |
ZFC3H1 is required for the nuclear retention and degradation of intronic polyadenylated (IPA) transcripts that contain intact 5' splice site (5'SS) motifs. ZFC3H1 sequesters mRNAs with 5'SS motifs into nuclear speckles to prevent their nuclear export, functioning in the same pathway as U1-70K (a component of the U1 snRNP). |
High-throughput sequencing of cellular fractions, reporter mRNA assays, siRNA knockdown, nuclear speckle disruption experiments, epistasis between ZFC3H1 and U1-70K |
RNA (New York, N.Y.) |
High |
35351812
|
| 2023 |
Mutational analysis of ZFC3H1 uncovered a direct ARS2-ZFC3H1 interaction via acidic-rich short linear motifs that compete with ZC3H18 for a common ARS2 epitope. This reveals a separate PAXT branch targeting short adenylated RNAs and explains how ZC3H18 simultaneously promotes NEXT while antagonizing PAXT activity. |
Site-directed mutagenesis, Co-IP, competitive binding assays, RNA-seq after KD/KO |
Cell reports |
Medium |
37889751
|
| 2023 |
ZFC3H1 is required for PAXT recruitment to transcription start sites (TSSs) of hundreds of genes; loss of ZFC3H1 abolishes recruitment of all PAXT subunits including PAPγ to TSSs and concomitantly increases the abundance of PROMPTs at those sites. ZFC3H1, MTR4, and PAPγ are all implicated in polyadenylation of PROMPTs. |
ChIP-seq / genome-wide binding mapping of ZFC3H1, RBM27, and PAPγ; ZFC3H1 KO with RNA-seq; proteomics |
Nature communications |
High |
37875486
|
| 2024 |
ZFC3H1 is co-transcriptionally loaded onto the first exon/intron of RNA precursors in a 'closed' conformation that blocks exosome recruitment. Upon RNA processing, short RNAs with fewer exons recruit transient PAXT components ZC3H3 and RBM26/27 to the 3' end, triggering ZFC3H1 'opening' and subsequent exosomal degradation, whereas longer RNAs with more exons are directed to nuclear export. This establishes a decoupled loading-and-activation mechanism for ZFC3H1 that pre-configures RNA fate. |
iCLIP/eCLIP mapping, domain mutant analysis, Co-IP, RNA-seq fractionation, nascent RNA analysis |
Molecular cell |
High |
39461342
|
| 2024 |
YTHDC1 and YTHDC2 (YTH-domain m6A reader proteins) interact with ZFC3H1 and U1-70K, and are required for nuclear retention of mRNAs with intact 5'SS motifs. Disruption of m6A deposition inhibits nuclear retention of these transcripts and their accumulation in YTHDC1-enriched foci adjacent to nuclear speckles. |
Co-IP (ZFC3H1 with YTHDC1/2), siRNA knockdown, reporter mRNA assays, RNA FISH, m6A inhibition experiments |
Life science alliance |
Medium |
39626965
|
| 2014 |
ZFC3H1 (also known as CCDC131/CSRC2) was identified as a direct binding protein of Celastramycin A by affinity pull-down screening. Knockdown of ZFC3H1 reduced TNFα-induced IL-8 expression, and reporter assays showed ZFC3H1 participates in transcriptional activation of IL-8. UV-irradiation experiments suggested ZFC3H1 may indirectly interact with ERCC1 in an activated DNA repair complex. |
Celastramycin A affinity pull-down screen, siRNA knockdown, IL-8 reporter assay, Co-IP suggestion |
PloS one |
Medium |
25268596
|
| 2022 |
ZFC3H1 participates in human telomerase RNA (hTR) biogenesis via pathways related to the polyadenylated RNA degradation mechanism, as determined by knockdown experiments examining hTR isoforms and localization. |
siRNA knockdown, RT-PCR analysis of hTR isoforms, cellular fractionation |
Biomedicines |
Low |
35740297
|
| 2024 |
ZFC3H1 protein competes with lncRNA MSL3P1 for binding to CUL3 mRNA; MSL3P1 prevents ZFC3H1-mediated degradation and cytoplasmic export blockade of CUL3 mRNA by competitive binding, demonstrating ZFC3H1's role in targeting specific mRNAs for exosomal degradation and nuclear retention. |
RNA immunoprecipitation, siRNA knockdown of ZFC3H1, RNA pull-down competition assays, cellular fractionation |
Molecular cancer research : MCR |
Low |
38718076
|