Fantastic collaborative effort within the @sfb-tpd-vienna.bsky.social consortium funded by @fwf-at.bsky.social, @viennabiocenter.bsky.social, and beyond.

Congratulations to co-first authors Irene Schwartz and Valentina Budroni, and to all co-authors at @maxperutzlabs.ac.at , @impvienna.bsky.social sky.social, @univie.ac.at e.ac.at, @tuwien.at en.at.

We combined CRISPR screens, TurboID proximity proteomics, in vitro reconstituted ubiquitination assays and direct binding studies, as well as mutREAD mutational signature sequencing: building this mechanistic picture from genetic to biochemical to clinical level.

Loss of UBR5 or HUWE1 increased A3-driven mutagenesis in cancer cell lines. In line with this, UBR5 and HUWE1 mutations in patient cancer genome data correlated with specially increased APOBEC3-driven mutational signatures, whereas mutations in other E3s did not.

This ensures selective targeting of nuclear A3s that are not engaged in antiviral RNA binding, while leaving cytosolic, antiviral A3 family members untouched. A quality-control checkpoint that balances innate immunity against genome integrity.

Degradation is coupled to nuclear localization through a single molecular switch: RNA binding. A3B and A3H-I that bind cellular RNAs are retained in the cytosol and shielded from the E3 ligases. When RNA binding is lost, they enter the nucleus and simultaneously become substrates for degradation.

A3B and A3H-I are major drivers of cancer mutation signatures, found in >50% of all cancer genomes. Yet they are normally kept at low levels in cells. How? Three ubiquitin E3 ligases (UBR4, UBR5, and HUWE1) actively mark them for proteasomal degradation.

The key determinant is APOBEC3 binding of cellular structured RNAs, which simultaneously controls their nuclear localization and shields them from E3 ligase-driven degradation.

Excellent collaboration with the labs of: @gekaragoz.bsky.social, @clausenlab.bsky.social, @haselbachlab.bsky.social,and x.com/MencheLab

Read the press release for the general public here:
www.maxperutzlabs.ac.at/news/latest-...

Our paper is out in @natcomms.nature.com! APOBEC3s drive mutagenesis in cancer. We uncover a novel pathway keeping them in check. The key is APOBEC3 binding of cellular RNAs, which simultaneously controls their nuclear localization and shields them from degradation.

Read it here: rdcu.be/e4qaa

We show that ERH and its associated RNA processing factors prevent intron retention in AU-rich regions of JAK2 transcripts. Loss of this regulation blocks JAK2 protein production and disrupts IFNγ signaling.

In great collaboration with the labs of @ameressl.bsky.social‬, Falk Butter, @reneketting.bsky.social‬, @mixmue.bsky.social‬, and @johanneszuber.bsky.social

Press release: bsky.app/profile/maxp...

Our latest study is now out in @narjournal.bsky.social‬: we identify a post-transcriptional bottleneck in interferon gamma signaling that hinges on proper maturation of JAK2 mRNA.
Paper: academic.oup.com/nar/article/...

TRIM52 maintains cellular fitness and is under tight proteolytic control by multiple giant E3 ligases - Nature Communications Despite not conserved in all mammals, TRIM52 is crucial for fitness in human cells. Here, the authors show that TRIM52 interacts with the DNA repair machinery to prevent cell-cycle arrest, and that TR...

We uncover how TRIM52 helps protect genome integrity by limiting topoisomerase 2 damage — and how its own levels are controlled by a multi-ligase degradation system. www.nature.com/articles/s41.... www.maxperutzlabs.ac.at/news/latest-.... @maxperutzlabs.bsky.social @sfb-tpd-vienna.bsky.social

New paper out in @natcomms.nature.com! A surprising story of a "non-conserved" protein that's vital for human cell fitness! Fantastic work by Alexandra Shulkina in collaboration with the @lcochella.bsky.social & @clausenlab.bsky.social labs.