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Synovial sarcoma X breakpoint 1 protein uses a cryptic groove to selectively recognize H2AK119Ub nucleosomes

Zebin Tong1, Huasong Ai2,3, Ziyu Xu1

  • 1Tsinghua-Peking Center for Life Sciences, Ministry of Education Key Laboratory of Bioorganic Phosphorus Chemistry and Chemical Biology, Center for Synthetic and Systems Biology, Department of Chemistry, Tsinghua University, Beijing, China.

Nature Structural & Molecular Biology
|January 4, 2024
PubMed

Insights

Synovial sarcoma

Area of Science:

  • Molecular biology
  • Cancer research
  • Structural biology

Background:

  • The SS18-SSX1 oncoprotein drives synovial sarcoma by mislocalizing the BAF complex.
  • SSX1's recognition of H2AK119Ub nucleosomes is crucial but mechanistically unclear.
  • The lack of canonical ubiquitin-binding domains in SSX1 poses a puzzle.

Purpose of the Study:

  • To elucidate the mechanism by which SSX1 recognizes H2AK119Ub nucleosomes.
  • To determine the structural basis for SSX1-nucleosome interaction.
  • To understand how this interaction contributes to synovial sarcoma pathogenesis.

Main Methods:

  • Cryo-electron microscopy (cryo-EM) to determine the structure of SSX1 bound to H2AK119Ub nucleosomes.
  • In vitro biochemical assays to validate binding interactions.
  • Cellular assays to assess functional consequences.

Main Results:

  • Determined the 3.1-Å cryo-EM structure of SSX1 bound to H2AK119Ub nucleosomes.
  • Discovered a unique binding mode involving a cryptic basic groove on the nucleosome, independent of canonical ubiquitin-binding domains.
  • Demonstrated that SSX1 binding induces DNA unwrapping at nucleosome entry/exit sites.

Conclusions:

  • SSX1 employs an unconventional mechanism to recognize ubiquitinated nucleosomes.
  • This unique recognition facilitates the aberrant recruitment of the BAF complex to Polycomb-repressed regions.
  • The findings provide insights into SS18-SSX1-driven oncogenesis in synovial sarcoma.

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