DNA Mismatch Repair Interacts with CAF-1- and ASF1A-H3-H4-dependent Histone (H3-H4)2 Tetramer Deposition

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Elena Rodriges Blanko1, Lyudmila Y Kadyrova1, Farid A Kadyrov2

  • 1From the Department of Biochemistry and Molecular Biology, Southern Illinois University, School of Medicine, Carbondale, Illinois 62901.

The Journal of Biological Chemistry
|March 6, 2016
PubMed

Insights

DNA mismatch repair (MMR) occurs before DNA is packaged into nucleosomes. Histone deposition by CAF-1 and ASF1A is compatible with MMR and prevents degradation of newly synthesized DNA strands.

Area of Science:

  • Molecular Biology
  • Genetics
  • Epigenetics

Background:

  • DNA mismatch repair (MMR) is crucial for genome stability and cancer prevention.
  • The interaction between MMR and the chromatin environment, particularly during replication-coupled nucleosome assembly, is not well understood.
  • Replication-coupled nucleosome assembly involves CAF-1-dependent histone (H3-H4)2 tetramer deposition via the ASF1A-H3-H4 complex.

Purpose of the Study:

  • To investigate the interactions between human MMR and CAF-1/ASF1A-mediated histone tetramer deposition using reconstituted systems.
  • To determine the impact of histone deposition on MMR efficiency and vice versa.
  • To elucidate the role of histone deposition in protecting newly synthesized DNA strands during MMR.

Main Methods:

  • Utilized reconstituted human systems to study MMR in conjunction with CAF-1 and ASF1A-H3-H4-dependent histone tetramer deposition.
  • Assessed the effect of MutSα on the packaging of DNA mismatches into tetrasomes.
  • Examined the influence of histone tetramer deposition on MMR reactions involving DNA polymerase δ (Pol δ) and DNA polymerase ϵ (Pol ϵ).

Main Results:

  • MutSα inhibits the CAF-1 and ASF1A-H3-H4-dependent packaging of DNA mismatches into tetrasomes, suggesting MMR precedes nucleosome assembly.
  • CAF-1 and ASF1A-H3-H4-dependent histone tetramer deposition does not impede MMR reactions.
  • Histone tetramer deposition suppresses the degradation of the discontinuous strand during Pol δ- and Pol ϵ-dependent MMR.

Conclusions:

  • MMR likely occurs before the newly synthesized DNA is packaged into nucleosomes.
  • Histone (H3-H4)2 tetramer deposition, mediated by CAF-1 and ASF1A, is compatible with MMR.
  • Histone deposition protects the discontinuous daughter strand from excessive degradation by the MMR machinery, contributing to genome integrity.
Keywords:
DNA mismatch repairDNA polymeraseDNA replicationcancergenomic instabilityhistonehistone chaperonemutL homolog 1 (MLH1)proliferating cell nuclear antigen (PCNA)replication factor C (RFC)

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