SUMO fosters assembly and functionality of the MutSγ complex to facilitate meiotic crossing over

Wei He, Gerrik F. Verhees, Nikhil Bhagwat, Ye Yang, Dhananjaya S. Kulkarni, Zane Lombardo, Sudipta Lahiri, Pritha Roy, Jiaming Zhuo, Brian Dang, Andriana Snyder, Shashank Shastry, Michael Moezpoor, Lilly Alocozy, Kathy Gyehyun Lee, Daniel Painter, Ishita Mukerji, Neil Hunter

Research output: Contribution to journalArticlepeer-review

Abstract

Crossing over is essential for chromosome segregation during meiosis. Protein modification by SUMO is implicated in crossover control, but pertinent targets have remained elusive. Here we identify Msh4 as a target of SUMO-mediated crossover regulation. Msh4 and Msh5 constitute the MutSγ complex, which stabilizes joint-molecule (JM) recombination intermediates and facilitates their resolution into crossovers. Msh4 SUMOylation enhances these processes to ensure that each chromosome pair acquires at least one crossover. Msh4 is directly targeted by E2 conjugase Ubc9, initially becoming mono-SUMOylated in response to DNA double-strand breaks, then multi/poly-SUMOylated forms arise as homologs fully engage. Mechanistically, SUMOylation fosters interaction between Msh4 and Msh5. We infer that initial SUMOylation of Msh4 enhances assembly of MutSγ in anticipation of JM formation, while secondary SUMOylation may promote downstream functions. Regulation of Msh4 by SUMO is distinct and independent of its previously described stabilization by phosphorylation, defining MutSγ as a hub for crossover control.

Original languageEnglish (US)
Pages (from-to)2073-2088.e3
JournalDevelopmental Cell
Volume56
Issue number14
DOIs
StatePublished - Jul 26 2021

Keywords

  • aneuploidy
  • chromosome segregation
  • crossing over
  • DNA repair
  • double-strand break
  • homologous recombination
  • meiosis
  • MutS
  • protein modification
  • SUMO

ASJC Scopus subject areas

  • Molecular Biology
  • Biochemistry, Genetics and Molecular Biology(all)
  • Developmental Biology
  • Cell Biology

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