Ulrich Hohmann
@hohmannulrich.bsky.social
Lastly, I’m excited to join @imbmainz.bsky.social in 2026 to start my own lab. We'll explore new mechanisms in eukaryotic gene expression, leveraging ‘evolutionary play’ to uncover how regulation, repurposing, and hijacking shape RNA biology. tinyurl.com/y4x29ctt
Thanks for reading! 20/20
Thanks for reading! 20/20
Research
IMB Mainz
tinyurl.com
November 19, 2025 at 11:22 PM
Lastly, I’m excited to join @imbmainz.bsky.social in 2026 to start my own lab. We'll explore new mechanisms in eukaryotic gene expression, leveraging ‘evolutionary play’ to uncover how regulation, repurposing, and hijacking shape RNA biology. tinyurl.com/y4x29ctt
Thanks for reading! 20/20
Thanks for reading! 20/20
And of course also a big ‘Thank you!’ to colleagues and support at @imbavienna.bsky.social, @impvienna.bsky.social, @viennabiocenter.bsky.social and for funding to @boehringerglobal.bsky.social, @erc.europa.eu, and my postdoc fellowships from @embo.org and Marie Skłodowska-Curie Actions
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November 19, 2025 at 11:22 PM
And of course also a big ‘Thank you!’ to colleagues and support at @imbavienna.bsky.social, @impvienna.bsky.social, @viennabiocenter.bsky.social and for funding to @boehringerglobal.bsky.social, @erc.europa.eu, and my postdoc fellowships from @embo.org and Marie Skłodowska-Curie Actions
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This was a quite a journey, and would not have been possible without my mentors @juliusbrennecke.bsky.social & Clemens, my colleagues in the Brennecke and @plaschkalab.bsky.social labs, and the institutional support at the @viennabiocenter.bsky.social. 18/
November 19, 2025 at 11:22 PM
This was a quite a journey, and would not have been possible without my mentors @juliusbrennecke.bsky.social & Clemens, my colleagues in the Brennecke and @plaschkalab.bsky.social labs, and the institutional support at the @viennabiocenter.bsky.social. 18/
Finally, we test the linearity of this model through IP-MS of UAP56 mutants. If we perturb TREX-2 binding (UAP56 mutant M1) -> UAP56 accumulates on mRNPs. THO binding (M2) -> UAP56 depletes from mRNPs. THO+TREX-2 binding (M3) -> mirrors loss of THO binding alone. 17/
November 19, 2025 at 11:22 PM
Finally, we test the linearity of this model through IP-MS of UAP56 mutants. If we perturb TREX-2 binding (UAP56 mutant M1) -> UAP56 accumulates on mRNPs. THO binding (M2) -> UAP56 depletes from mRNPs. THO+TREX-2 binding (M3) -> mirrors loss of THO binding alone. 17/
Taken together, we find that UAP56 is an “mRNP packaging mark”, that controls important aspects of the nuclear events of the mRNA export pathway: disassembly of TREX, docking of the mRNP at the NPC, and release into the NPC. 16/
November 19, 2025 at 11:22 PM
Taken together, we find that UAP56 is an “mRNP packaging mark”, that controls important aspects of the nuclear events of the mRNA export pathway: disassembly of TREX, docking of the mRNP at the NPC, and release into the NPC. 16/
We can visualize this TREX-2 activity also directly: we bead-immobilize UAP56–ADP-Pi–RNA complexes. Incubation with TREX-2 releases UAP56 from the RNA. In contrast, as expected, the THO complex does not have any effect on clamped UAP56. 15/
November 19, 2025 at 11:22 PM
We can visualize this TREX-2 activity also directly: we bead-immobilize UAP56–ADP-Pi–RNA complexes. Incubation with TREX-2 releases UAP56 from the RNA. In contrast, as expected, the THO complex does not have any effect on clamped UAP56. 15/
A highly conserved ‘wedge’ loop of the TREX-2 subunit GANP binds the nucleotide, which is still bound to UAP56’s RecA1 lobe (unusual for an open DExD ATPase). In vitro ATPase assays show a dramatic stimulation of UAP56’s ATPase rate by TREX-2. So TREX-2 promotes RNA release from UAP56! 14/
November 19, 2025 at 11:22 PM
A highly conserved ‘wedge’ loop of the TREX-2 subunit GANP binds the nucleotide, which is still bound to UAP56’s RecA1 lobe (unusual for an open DExD ATPase). In vitro ATPase assays show a dramatic stimulation of UAP56’s ATPase rate by TREX-2. So TREX-2 promotes RNA release from UAP56! 14/
However, to complete export, the mRNP must subsequently be released again from TREX-2. How does this happen? To our surprise, in our cryo-EM structure of the UAP56–TREX-2 complex UAP56 was not in an RNA-bound, closed conformation, but instead open?! 13/
November 19, 2025 at 11:22 PM
However, to complete export, the mRNP must subsequently be released again from TREX-2. How does this happen? To our surprise, in our cryo-EM structure of the UAP56–TREX-2 complex UAP56 was not in an RNA-bound, closed conformation, but instead open?! 13/
In cells we show: the identified interfaces are critical for cell viability. In addition, perturbing the UAP56–TREX-2 interaction leads to mRNA export defects, as assessed (amongst other assays) through polyA-FISH in human K562 cells with a knockout-rescue setup for the TREX-2 subunit PCID2. 12/
November 19, 2025 at 11:22 PM
In cells we show: the identified interfaces are critical for cell viability. In addition, perturbing the UAP56–TREX-2 interaction leads to mRNA export defects, as assessed (amongst other assays) through polyA-FISH in human K562 cells with a knockout-rescue setup for the TREX-2 subunit PCID2. 12/
Could TREX-2 be a landing pad at the NPC for UAP56-bound, export ready mRNPs? Biochemically we show that UAP56 does indeed bind TREX-2 and solved a cryo-EM strcture of the complex. This revealed a role for the conserved UAP56 NTD in TREX-2 binding. 11/
November 19, 2025 at 11:22 PM
Could TREX-2 be a landing pad at the NPC for UAP56-bound, export ready mRNPs? Biochemically we show that UAP56 does indeed bind TREX-2 and solved a cryo-EM strcture of the complex. This revealed a role for the conserved UAP56 NTD in TREX-2 binding. 11/
Besides known UAP56 interactors we find some novel ones. Among them: GANP and PCID2, two subunits of the TREX-2 complex. A big surprise to us! TREX-2 (sharing only its name with TREX) is involved in mRNA export and bound to the basket of the nuclear pore complex (NPC)… 10/
November 19, 2025 at 11:22 PM
Besides known UAP56 interactors we find some novel ones. Among them: GANP and PCID2, two subunits of the TREX-2 complex. A big surprise to us! TREX-2 (sharing only its name with TREX) is involved in mRNA export and bound to the basket of the nuclear pore complex (NPC)… 10/
So: TREX disassembly yields mature, export-ready mRNPs, marked by clamped UAP56. Could clamped UAP56 be a molecular mark controlling final steps of nuclear export? To find new UAP56 interactors we used AlphaFold2 Multimer to screen the nuclear UAP56 interactome. 9/
November 19, 2025 at 11:22 PM
So: TREX disassembly yields mature, export-ready mRNPs, marked by clamped UAP56. Could clamped UAP56 be a molecular mark controlling final steps of nuclear export? To find new UAP56 interactors we used AlphaFold2 Multimer to screen the nuclear UAP56 interactome. 9/
Remarkably, SARNP disassembles THO-UAP56 in the presence of ATP and RNA in vitro. And in endogenous mRNPs? We purified endogenous TREX-bound mRNPs. Again, a minimal SARNP construct (including the UCM) could dissociate the mRNP from THO. 8/
November 19, 2025 at 11:22 PM
Remarkably, SARNP disassembles THO-UAP56 in the presence of ATP and RNA in vitro. And in endogenous mRNPs? We purified endogenous TREX-bound mRNPs. Again, a minimal SARNP construct (including the UCM) could dissociate the mRNP from THO. 8/
Is RNA clamping of UAP56 regulated? We identify SARNP as a ‘clamping factor’. It has a motif we named ‘UCM’, which binds adjacent to the newly identified N-UBM binding site on UAP56. N-UBM and UCM cooperatively enhance UAP56’s affinity for RNA, this might aid directionality of mRNP remodelling. 7/
November 19, 2025 at 11:22 PM
Is RNA clamping of UAP56 regulated? We identify SARNP as a ‘clamping factor’. It has a motif we named ‘UCM’, which binds adjacent to the newly identified N-UBM binding site on UAP56. N-UBM and UCM cooperatively enhance UAP56’s affinity for RNA, this might aid directionality of mRNP remodelling. 7/
Upon RNA clamping UAP56 hydrolyses ATP, and the resulting UAP56–ADP-Pi–RNA complexes are remarkably stable, for example persisting in size exclusion chromatography experiments. This suggests that UAP56 can be ‘deposited’ on the mRNA as a maturation mark. 6/
November 19, 2025 at 11:22 PM
Upon RNA clamping UAP56 hydrolyses ATP, and the resulting UAP56–ADP-Pi–RNA complexes are remarkably stable, for example persisting in size exclusion chromatography experiments. This suggests that UAP56 can be ‘deposited’ on the mRNA as a maturation mark. 6/
Could the conformational change in UAP56 between its open and its RNA-clamped state play a role? Turns out it does: Open UAP56 binds THO, RNA-clamped UAP56 has no measurable affinity! This suggests that clamping of UAP56 releases THO from the mRNP. 5/
November 19, 2025 at 11:22 PM
Could the conformational change in UAP56 between its open and its RNA-clamped state play a role? Turns out it does: Open UAP56 binds THO, RNA-clamped UAP56 has no measurable affinity! This suggests that clamping of UAP56 releases THO from the mRNP. 5/
We found that UAP56 binds to the two known UAP56-binding motifs (UBMs) in mRNP export adapters, such as ALYREF, in distinct ways. The C-UBM binds the previously known site on UAP56’s RecA1 lobe, but, unexpectedly, the N-UBM binds a distinct site on the RecA2 lobe. 4/
November 19, 2025 at 11:22 PM
We found that UAP56 binds to the two known UAP56-binding motifs (UBMs) in mRNP export adapters, such as ALYREF, in distinct ways. The C-UBM binds the previously known site on UAP56’s RecA1 lobe, but, unexpectedly, the N-UBM binds a distinct site on the RecA2 lobe. 4/
THO binds to maturing mRNPs (=mRNA+proteins), directing them into the mRNA export pathway. Yet THO must again dissociate, to allow for subsequent steps in export. How? The connection between mRNP and THO is the DExD-box ATPase UAP56, which binds to UBM motifs in mRNP export adapters (like ALYREF).3/
November 19, 2025 at 11:22 PM
THO binds to maturing mRNPs (=mRNA+proteins), directing them into the mRNA export pathway. Yet THO must again dissociate, to allow for subsequent steps in export. How? The connection between mRNP and THO is the DExD-box ATPase UAP56, which binds to UBM motifs in mRNP export adapters (like ALYREF).3/
mRNA nuclear export is a key step in eukaryotic gene expression. While the key players had been discovered over the past decades, the structural basis for how these proteins remodel mRNAs for nuclear export was unclear. 2/
November 19, 2025 at 11:22 PM
mRNA nuclear export is a key step in eukaryotic gene expression. While the key players had been discovered over the past decades, the structural basis for how these proteins remodel mRNAs for nuclear export was unclear. 2/
Thanks a lot Yasin!
October 13, 2025 at 7:54 PM
Thanks a lot Yasin!
Shout-out also to my wonderful colleagues in the Hothorn / Brennecke / Plaschka labs, as well as to the great environment and many colleagues at the University of Geneva, @viennabiocenter.bsky.social, @impvienna.bsky.social, @imbavienna.bsky.social
October 12, 2025 at 8:19 PM
Shout-out also to my wonderful colleagues in the Hothorn / Brennecke / Plaschka labs, as well as to the great environment and many colleagues at the University of Geneva, @viennabiocenter.bsky.social, @impvienna.bsky.social, @imbavienna.bsky.social
This would have been impossible without the amazing support from my PhD mentor @structplantbio.bsky.social, and my postdoc mentors @juliusbrennecke.bsky.social and Clemens Plaschka (@plaschkalab.bsky.social)!
October 12, 2025 at 8:19 PM
This would have been impossible without the amazing support from my PhD mentor @structplantbio.bsky.social, and my postdoc mentors @juliusbrennecke.bsky.social and Clemens Plaschka (@plaschkalab.bsky.social)!