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PRINCIPAL PUBLICATION AND AUTHORS

The SPOC domain is a phosphoserine binding module that bridges transcription machinery with co- and post-transcriptional regulators, L.M. Appel (a,b,c), V. Franke (d), J. Benedum (a,b,c,e), I. Grishkovskaya (f), X. Strobl (c,e), A. Polyansky (f), G. Ammann (g), S. Platzer (c), A. Neudolt (c), A. Wunder (c), L. Walch (c), S. Kaiser (g), B. Zagrovic (f), K. Djinovic-Carugo (f,h,i), A. Akalin (d), D. Slade (a,b,c), Nat. Commun. 14, 166 (2023); https:/doi.org/10.1038/s41467-023-35853-1 (a) Department of Radiation Oncology, Medical University of Vienna (Austria) (b) Comprehensive Cancer Center, Medical University of Vienna (Austria) (c) Department of Medical Biochemistry, Medical University of Vienna (Austria) (d) The Berlin Institute for Medical Systems Biology, Max Delbrück Center (Germany) (e) Vienna Biocenter PhD Program, a Doctoral School of the University of Vienna and Medical University of Vienna (Austria) (f) Department of Structural and Computational Biology, Max Perutz Labs, University of Vienna (Austria) (g) Department of Pharmaceutical Chemistry, Goethe University Frankfurt (Germany) (h) Department of Biochemistry, Faculty of Chemistry and Chemical Technology, University of Ljubljana (Slovenia) (i) European Molecular Biology Laboratory (EMBL) Grenoble (France)

REFERENCES

[1] L.M. Appel et al., Genes Dev. 37(5-6), 140-170 (2023). [2] L.M. Appel et al., Nat. Commun. 12, 6078 (2021).

bind writers and readers of m6A, the most abundant mRNA modification. The primary anchoring point of RBM15 to the m6A writer complex is the subunit WTAP, which is bound by RBM15 SPOC in a phospho-serine- 14-dependant manner (Figure 16a). In contrast, SHARP binds the m6A reader protein FMR1 in a similar manner as SMRT/NCoR and Pol II CTD (Figure 16b,c). Loss of RBM15 or deletion of its SPOC domain results in a global reduction of m6A levels in mRNA (Figure 16d), which may have an influence on RNA stability, export and translation. While PHF3 and DIDO associate with the Pol II elongation complex to directly influence transcription, RBM15 and SHARP appear to coordinate post-transcriptional mRNA fate by recruiting m6A writers and readers, respectively.

Collectively, the study reveals that the SPOC domains of PHF3, DIDO, RBM15 and SHARP display different affinities and specificities for Pol II CTD phosphomarks based on their individual electrostatic surface potential patterns. Furthermore, SPOC domains engage with other phosphorylated binding partners such as NCoR/SMRT, WTAP and FMR1. This highlights the adaptable nature of SPOC as a phosphoserine reader, associating with the Pol II CTD, co-repressor complexes and the m6A writer and reader machinery. The multivalent interactions of SPOC domain proteins establish a crucial link between transcription and RNA metabolism, ensuring precise gene expression.

Fig. 16: Fluorescence anisotropy assays of (a) RBM15 SPOC and WTAP phospho-peptides and (b) SHARP SPOC and FMR1 phospho-peptides. c) Structural model of the SHARP SPOC-FMR1 phospho-serine-511 interaction. d) mRNA m6A levels in SPOC wild type and mutant cell lines.