Fission Yeast Methylenetetrahydrofolate Reductase Ensures Mitotic and Meiotic Chromosome Segregation Fidelity

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.

Association between MTHFR C677T and A1298C gene polymorphisms and maternal risk for Down syndrome

“…[7] In addition, dietary folates and related metabolic factors can also regulate MTHFR gene methylation and expression levels. [12,13] A recent study revealed that the fission yeast methylenetetrahydrofolate reductase protein (Met11) is important for maintaining the pericentromeric heterochromatin structure to ensure mitotic and meiotic chromosome segregation fidelity, [14] supporting the original hypothesis by James et al and suggesting that MTHFR polymorphisms promote changes in global DNA methylation during maternal meiosis leading to chromosomal non-disjunction and increasing the maternal risk to have children with DS. [6] In addition, both MTHFR C677T and A1298C polymorphisms have been linked to an increased risk of chromosome malsegregation in lymphocytes of mothers of DS children.…”

“…A recent study revealed that the fission yeast methylenetetrahydrofolate reductase protein (Met11) is important for maintaining the pericentromeric heterochromatin structure to ensure mitotic and meiotic chromosome segregation fidelity, [ 14 ] supporting the original hypothesis by James et al and suggesting that MTHFR polymorphisms promote changes in global DNA methylation during maternal meiosis leading to chromosomal non-disjunction and increasing the maternal risk to have children with DS. [ 6 ]…”

Resistance to Chemotherapeutic 5-Fluorouracil Conferred by Modulation of Heterochromatic Integrity through Ino80 Function in Fission Yeast

“…RNAi mutants host disruption of centromeric heterochromatin that compromises kinetochore function, resulting in hypersensitivity to microtubule depolymerizing drug thiabendazole (TBZ) [ 48 , 49 ]. To assess if the suppression of Δago1 and Δclr4 may similarly result in the TBZ hypersensitivity of these mutants, we performed serial dilution spotting assays on 8 and 15 µg/mL TBZ, to check TBZ sensitivity of the single and double mutants of 5-FU-resistant gene mutants combined with Δago1 and Δclr4 .…”

A systematic quantitative approach comprehensively defines domain-specific functional pathways linked toSchizosaccharomyces pombeheterochromatin regulation

“…While most of these factors were missed by the previous genome-wide studies, other research reported several links to methionine and SAM synthesis. Methylenetetrahydrofolate reductase Met11 plays a role in methionine regeneration through 5-MTHF generation and was noted to affect heterochromatin integrity (Lim et al, 2021). Additionally, SAM synthetase was among the SU(VAR) mutants displaying altered position effect of variegation in flies (Larsson et al, 1996) and was further shown to be crucial for silencing and perinuclear heterochromatin anchoring in worms (Towbin et al, 2012).…”