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Home > Research Leaders > T to Z > Suyang Zhang
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Suyang Zhang

Mechanism of transcription-coupled alternative splicing


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Splicing of precursor messenger RNA (pre-mRNA) is a ubiquitous hallmark of gene expression in all eukaryotes. Within the cell, splicing occurs simultaneously with pre-mRNA synthesis by RNA polymerase II (Pol II) and is mechanistically coupled to transcription. The choice of the splice sites is not always unique, as a single gene can give rise to multiple functionally distinct mRNA isoforms through alternative splicing. In fact, more than 95% of human genes are alternatively spliced, massively expanding the coding potential of our genome. Dysregulation of alternative splicing contributes to cancer pathogenesis and is under study as a biomarker of diseases. Our research aims to understand the mechanism governing alternative splice site selection and the crosstalk between the transcription and splicing machineries.

Regulation of alternative splicing is coupled with transcription
Regulation of alternative splicing is coupled with transcription

We recently determined the cryo-EM structure of the transcribing Pol II in complex with U1 snRNP, the first spliceosomal building block that engages pre-mRNA. The structure revealed for the first time a direct protein interaction between the transcription and splicing machineries within a large supercomplex and provided insights into how functional pairing of distant intron ends and spliceosome assembly can occur on the Pol II surface.

Cryo-EM structure of the transcribing Pol II-U1 snRNP complex
Cryo-EM structure of the transcribing Pol II-U1 snRNP complex

Our lab employs a multidisciplinary approach combining biochemical reconstitution, functional assays, structural biology and in vivo RNA sequencing to define the molecular basis of transcription-coupled alternative splicing. Our long-term research goal is to understand how the transcription and splicing machineries functionally interact to regulate gene expression.

Selected Papers

  • Zhang S, Aibara S, Vos S, Agafonov D, Lührmann R, Cramer P. (2021)
    Structure of a transcribing RNA polymerase II-U1 snRNP complex.
    Science 371: 305-309.
  • Zhang S, Tischer T & Barford D. (2019)
    Cyclin A2 degradation during the spindle assembly checkpoint requires multiple binding modes to the APC/C.
    Nature Communications 10: 3863.
  • Zhang S, Chang L, Alfieri C, Zhang Z, Yang J, Maslen S, Skehel M & Barford D. (2016)
    Molecular mechanism of APC/C activation by mitotic phosphorylation.
    Nature 533: 260-264.
  • Erzberger JP, Stengel F, Pellarin R, Zhang S, Schäfer T, Aylett CH, Cimermancic P, Boehringer D, Sali A, Aebersold R, Ban N. (2014)
    Molecular architecture of the 40S⋅eIF1⋅eIF3 translation initiation complex.
    Cell 158(5): 1123-35.

Group Members

  • Jacqueline Mills
  • Helen Zhang

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