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hMSH2-hMSH6 forms a hydrolysis-independent sliding clamp on mismatched DNA

S Gradia1, D Subramanian, T Wilson

  • 1Department of Microbiology and Immunology, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania 19107, USA.

Molecular Cell
|March 17, 1999
PubMed

Insights

Human DNA mismatch repair protein hMSH2-hMSH6 acts as a molecular switch. ATP binding allows it to slide along DNA, aiding in efficient and bidirectional DNA repair processes.

Area of Science:

  • Molecular biology
  • DNA repair mechanisms
  • Cellular signaling

Background:

  • The human MutS homologs, specifically hMSH2-hMSH6, are crucial for DNA mismatch recognition.
  • Adenosine nucleotide binding is known to regulate this process, suggesting a molecular switch function.

Purpose of the Study:

  • To investigate the mechanism of hMSH2-hMSH6 interaction with mismatched DNA.
  • To elucidate the role of ATP binding and exchange in DNA mismatch repair.
  • To understand how hMSH2-hMSH6 functions as a sliding clamp.

Main Methods:

  • Experiments involving blocked and circular DNA substrates.
  • Analysis of ATP-ADP exchange dynamics.
  • Conformational change studies of hMSH2-hMSH6.

Main Results:

  • ATP-induced release of hMSH2-hMSH6 from mismatched DNA is hindered by DNA end-blocking or circularization.
  • Mismatched DNA triggers ADP to ATP exchange within hMSH2-hMSH6.
  • This exchange induces a conformational shift, transforming hMSH2-hMSH6 into a sliding clamp for hydrolysis-independent diffusion.

Conclusions:

  • hMSH2-hMSH6 functions as a bidirectional DNA mismatch repair switch.
  • The protein acts as a sliding clamp, facilitating diffusion along the DNA backbone.
  • This mechanism, involving stochastic loading of multiple clamps, activates repair machinery and signaling effectors, akin to G protein switches.

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