Involvement of DNA mismatch repair in the maintenance of heterochromatic DNA stability in Saccharomyces cerevisiae

Abstract

Heterochromatin contains a significant part of nuclear DNA. Little is known about the mechanisms that govern heterochromatic DNA stability. We show here that in the yeast Saccharomyces cerevisiae (i) DNA mismatch repair (MMR) is required for the maintenance of heterochromatic DNA stability, (ii) MutLα (Mlh1-Pms1 heterodimer), MutSα (Msh2-Msh6 heterodimer), MutSβ (Msh2-Msh3 heterodimer), and Exo1 are involved in MMR at heterochromatin, (iii) Exo1-independent MMR at heterochromatin frequently leads to the formation of Pol ζ-dependent mutations, (iv) MMR cooperates with the proofreading activity of Pol ε and the histone acetyltransferase Rtt109 in the maintenance of heterochromatic DNA stability, (v) repair of base-base mismatches at heterochromatin is less efficient than repair of base-base mismatches at euchromatin, and (vi) the efficiency of repair of 1-nt insertion/deletion loops at heterochromatin is similar to the efficiency of repair of 1-nt insertion/deletion loops at euchromatin.

Examination of gene loss in the DNA mismatch repair pathway and its mutational consequences in a fungal phylum

“…Loss of genes in the RIP pathway in HLT could contribute to the elevated mutation rates we observed relative to LLT. The MMR pathway is required for maintaining heterochromatin stability in S. cerevisiae ; dysfunction in this pathway could potentially lead to genome instability within the HLT (Dahal et al 2017). MMR is more error prone in heterochromatin than euchromatin, likely due at least in part to mechanical accessibility of the MMR machinery (Dahal et al 2017; Sun et al 2016).…”

“…The MMR pathway is required for maintaining heterochromatin stability in S. cerevisiae ; dysfunction in this pathway could potentially lead to genome instability within the HLT (Dahal et al 2017). MMR is more error prone in heterochromatin than euchromatin, likely due at least in part to mechanical accessibility of the MMR machinery (Dahal et al 2017; Sun et al 2016). While base-base mismatches are repaired less efficiently in heterochromatin than in euchromatin, single nucleotide insertions and deletions are repaired with similar efficiency in euchromatin and heterochromatin (Dahal et al 2017); therefore, differences in chromatin structure could have contributed to some of the observed mutational differences but not to the observed differences in mononucleotide runs and microsatellite repeats.…”

Examination of Gene Loss in the DNA Mismatch Repair Pathway and Its Mutational Consequences in a Fungal Phylum

“…Loss of genes in the repeat-induced point pathway in HLT could contribute to the elevated mutation rates we observed relative to LLT. The MMR pathway is required for maintaining heterochromatin stability in S. cerevisiae ; dysfunction in this pathway could potentially lead to genome instability within the HLT ( Dahal et al 2017 ). MMR is more error prone in heterochromatin than euchromatin, likely due at least in part to mechanical accessibility of the MMR machinery ( Sun et al 2016 ; Dahal et al 2017 ).…”

“…The MMR pathway is required for maintaining heterochromatin stability in S. cerevisiae ; dysfunction in this pathway could potentially lead to genome instability within the HLT ( Dahal et al 2017 ). MMR is more error prone in heterochromatin than euchromatin, likely due at least in part to mechanical accessibility of the MMR machinery ( Sun et al 2016 ; Dahal et al 2017 ). Although base–base mismatches are repaired less efficiently in heterochromatin than in euchromatin, single-nucleotide insertions and deletions are repaired with similar efficiency in euchromatin and heterochromatin ( Dahal et al 2017 ); therefore, differences in chromatin structure could have contributed to some of the observed mutational differences but not to the observed differences in mononucleotide runs and microsatellite repeats.…”