Abstract
Methylenetetrahydrofolate reductase (MTHFR) is a key enzyme in the folate metabolic pathway, and its loss of function through polymorphisms is often associated with human conditions, including cancer, congenital heart disease, and Down syndrome. MTHFR is also required in the maintenance of heterochromatin, a crucial determinant of genomic stability and precise chromosomal segregation. Here, we characterize the function of a fission yeast gene met11+, which encodes a protein that is highly homologous to the mammalian MTHFR. We show that, although met11+ is not essential for viability, its disruption increases chromosome missegregation and destabilizes constitutive heterochromatic regions at pericentromeric, sub-telomeric and ribosomal DNA (rDNA) loci. Transcriptional silencing at these sites were disrupted, which is accompanied by the reduction in enrichment of histone H3 lysine 9 dimethylation (H3K9me2) and binding of the heterochromatin protein 1 (HP1)-like Swi6. The met11 null mutant also dominantly disrupts meiotic fidelity, as displayed by reduced sporulation efficiency and defects in proper partitioning of the genetic material during meiosis. Interestingly, the faithful execution of these meiotic processes is synergistically ensured by cooperation among Met11, Rec8, a meiosis-specific cohesin protein, and the shugoshin protein Sgo1, which protects Rec8 from untimely cleavage. Overall, our results suggest a key role for Met11 in maintaining pericentromeric heterochromatin for precise genetic inheritance during mitosis and meiosis.
Highlights
Eukaryotic DNA is packaged by histones into chromatin, with approximately 146 base pairs of DNA wrapped around eight histone molecules in a fundamental complex referred to as the nucleosome [1]
We explored the role of the fission yeast Methylenetetrahydrofolate reductase (MTHFR), Met11, on chromosome segregation
We found that a loss of Met11 inhibited precise chromosome segregation and was associated with a disruption in centromeric heterochromatin
Summary
Eukaryotic DNA is packaged by histones into chromatin, with approximately 146 base pairs (bp) of DNA wrapped around eight histone molecules in a fundamental complex referred to as the nucleosome [1]. Chromatin can be broadly divided into two types: (1) loosely packaged and transcriptionally competent euchromatin, which encompasses most of the genome; and (2) heterochromatin, a transcriptionally silenced and structurally more compact type that shows a low rate of nucleosomal exchange [2,3]. A loss of heterochromatin integrity improves accessibility of the transcriptional machinery to the DNA, resulting in an increased expression of non-coding transcripts [8,9]. It can result in an increase in DNA double-stranded break formation [10,11], as a consequence of a disruption to activity of effectors that induce chromatin compaction, for example, histone deacetylases, key enzymatic components of silenced chromatin
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