title: Preferential Protection of Genetic Fidelity within Open Chromatin by the Mismatch Repair Machinery.
abstract: Epigenetic systems are well known for the roles they play in regulating the differential expression of the same genome in different cell types. However, epigenetic systems can also directly impact genomic integrity by protecting genetic sequences. Using an experimental evolutionary approach, we studied rates of mutation in the fission yeast Schizosaccharomyces pombe strains that lacked genes encoding several epigenetic regulators or mismatch repair components. We report that loss of a functional mismatch repair pathway in S. pombe resulted in the preferential enrichment of mutations in euchromatin, indicating that the mismatch repair machinery preferentially protected genetic fidelity in euchromatin. This preference is probably determined by differences in the accessibility of chromatin at distinct chromatin regions, which is supported by our observations that chromatin accessibility positively correlated with mutation rates in S. pombe or human cancer samples with deficiencies in mismatch repair. Importantly, such positive correlation was not observed in S. pombe strains or human cancer samples with functional mismatch repair machinery.
authors.affiliation: From the Tsinghua University-Peking University-National Institute of Biological Sciences Joint Graduate Program, School of Life Sciences, Tsinghua University, Beijing 100084, the National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, the National Institute of Biological Sciences, Beijing 102206, and.
authors.forename: Lue
authors.initials: L
authors.lastname: Sun
authors.affiliation: the National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101.
authors.forename: Yan
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: the National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101.
authors.forename: Zhuqiang
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: the National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101.
authors.forename: Yong
authors.initials: Y
authors.lastname: Zheng
authors.affiliation: the National Institute of Biological Sciences, Beijing 102206, and.
authors.forename: Lilin
authors.initials: L
authors.lastname: Du
authors.affiliation: the National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, the College of Life Sciences, University of Chinese Academy of Sciences, Beijing 100049, China zhubing@ibp.ac.cn.
authors.forename: Bing
authors.initials: B
authors.lastname: Zhu
mesh_terms: D002843:Chromatin / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D053843:DNA Mismatch Repair; D044127:Epigenesis, Genetic; D015966:Gene Expression Regulation, Fungal; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D009154:Mutation; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism*; D012568:Schizosaccharomyces / Q000235:genetics / Q000378:metabolism*
chemical_list: D002843:Chromatin
keywords: DNA repair; chromatin; chromatin regulation; heterochromatin; mutagenesis mechanism