Yeast mismatch repair components are required for stable inheritance of gene silencing

• Alterations in epigenetic silencing have been associated with ageing and tumour formation. Although substantial efforts have been made towards understanding the mechanisms of gene silencing, novel regulators in this process remain to be identified. To systematically search for components governing epigenetic silencing, we developed a genome-wide silencing screen for yeast (Saccharomyces cerevisiae) silent mating type locus HMR. Unexpectedly, the screen identified the mismatch repair (MMR) components Pms1, Mlh1, and Msh2 as being required for silencing at this locus. We further found that the identified genes were also required for proper silencing in telomeres. More intriguingly, the MMR mutants caused a redistribution of Sir2 deacetylase, from silent mating type loci and telomeres to rDNA regions. As a consequence, acetylation levels at histone positions H3K14, H3K56, and H4K16 were increased at silent mating type loci and telomeres but were decreased in rDNA regions. Moreover, knockdown of MMR components in human HEK293T cells increased subtelomeric DUX4 gene expression. Our work reveals that MMR components are required for stable inheritance of gene silencing patterns and establishes a link between the MMR machinery and the control of epigenetic silencing. Author summary During aging, gene silencing also decreases and it has been hypothesized that the collapse of epigenetic control networks may in part explain age-related diseases. For example, changes in epigenetic silencing are linked with different stages of tumor formation and progression. Great efforts have been made on investigating the mechanisms of establishment and maintenance silencing at silent mating cassettes in yeast. In this work, by applying a genome-wide silencing screening approach, we identified the conserved subunits of the mismatch repair (MMR) machinery (Pms1, Mlh1 and Msh2) as new components of the epigenetic silencing regulation machinery in yeast. We also found that depletion of mismatch repair subunits (Mlh1 and Msh2) led to impaired telomere-length related expression in mammalian cells. This indicates that these components probably have an evolutionarily conserved role on influencing gene silencing from yeast to humans. Further studies the functional roles of these MMR components on epigenetic silencing in mammalian model systems or relevant cancer patient samples will increase our understanding of MMR-related oncogenesis.

Ämnesord

MEDICIN OCH HÄLSOVETENSKAP  -- Medicinska och farmaceutiska grundvetenskaper -- Medicinsk genetik (hsv//swe)

MEDICAL AND HEALTH SCIENCES  -- Basic Medicine -- Medical Genetics (hsv//eng)

Nyckelord

origin recognition complex

saccharomyces-cerevisiae

DNA-replication

homologous recombination

strand breaks

sir proteins

telomeres

chromatin

establishment

localization

Genetics & Heredity

Publikations- och innehållstyp

ref (ämneskategori)

art (ämneskategori)