hMSH4-hMSH5 recognizes Holliday Junctions and forms a meiosis-specific sliding clamp that embraces homologous chromosomes

Mol Cell. 2004 Aug 13;15(3):437-51. doi: 10.1016/j.molcel.2004.06.040.


Five MutS homologs (MSH), which form three heterodimeric protein complexes, have been identified in eukaryotes. While the human hMSH2-hMSH3 and hMSH2-hMSH6 heterodimers operate primarily in mitotic mismatch repair (MMR), the biochemical function(s) of the meiosis-specific hMSH4-hMSH5 heterodimer is unknown. Here, we demonstrate that purified hMSH4-hMSH5 binds uniquely to Holliday Junctions. Holliday Junctions stimulate the hMSH4-hMSH5 ATP hydrolysis (ATPase) activity, which is controlled by Holliday Junction-provoked ADP-->ATP exchange. ATP binding by hMSH4-hMSH5 induces the formation of a hydrolysis-independent sliding clamp that dissociates from the Holliday Junction crossover region, embracing two homologous duplex DNA arms. Fundamental differences between hMSH2-hMSH6 and hMSH4-hMSH5 Holliday Junction recognition are detailed. Our results support the attractive possibility that hMSH4-hMSH5 stabilizes and preserves a meiotic bimolecular double-strand break repair (DSBR) intermediate.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adenosine Triphosphatases / metabolism
  • Cell Cycle Proteins / chemistry
  • Cell Cycle Proteins / isolation & purification
  • Cell Cycle Proteins / metabolism*
  • Chromosomes, Human / metabolism*
  • DNA, Cruciform / metabolism*
  • Dimerization
  • Humans
  • Meiosis / physiology*
  • Proteins / chemistry
  • Proteins / isolation & purification
  • Proteins / metabolism*


  • Cell Cycle Proteins
  • DNA, Cruciform
  • MSH4 protein, human
  • MSH5 protein, human
  • Proteins
  • Adenosine Triphosphatases