title: Intersection of calorie restriction and magnesium in the suppression of genome-destabilizing RNA-DNA hybrids.
abstract: Dietary calorie restriction is a broadly acting intervention that extends the lifespan of various organisms from yeast to mammals. On another front, magnesium (Mg2+) is an essential biological metal critical to fundamental cellular processes and is commonly used as both a dietary supplement and treatment for some clinical conditions. If connections exist between calorie restriction and Mg2+is unknown. Here, we show that Mg2+, acting alone or in response to dietary calorie restriction, allows eukaryotic cells to combat genome-destabilizing and lifespan-shortening accumulations of RNA-DNA hybrids, or R-loops. In an R-loop accumulation model of Pbp1-deficient Saccharomyces cerevisiae, magnesium ions guided by cell membrane Mg2+transporters Alr1/2 act via Mg2+-sensitive R-loop suppressors Rnh1/201 and Pif1 to restore R-loop suppression, ribosomal DNA stability and cellular lifespan. Similarly, human cells deficient in ATXN2, the human ortholog of Pbp1, exhibit nuclear R-loop accumulations repressible by Mg2+in a process that is dependent on the TRPM7 Mg2+transporter and the RNaseH1 R-loop suppressor. Thus, we identify Mg2+as a biochemical signal of beneficial calorie restriction, reveal an R-loop suppressing function for human ATXN2 and propose that practical magnesium supplementation regimens can be used to combat R-loop accumulation linked to the dysfunction of disease-linked human genes.
authors: Department of Laboratory Medicine and Pathobiology, Faculty of Medicine, University of Toronto, 1 King's College Circle, Toronto, ON M5S 1A8, Canada.
authors: Karan J
authors: KJ
authors: Abraham
authors: Department of Laboratory Medicine and Pathobiology, Faculty of Medicine, University of Toronto, 1 King's College Circle, Toronto, ON M5S 1A8, Canada.
authors: Janet N Y
authors: JN
authors: Chan
authors: Department of Laboratory Medicine and Pathobiology, Faculty of Medicine, University of Toronto, 1 King's College Circle, Toronto, ON M5S 1A8, Canada.
authors: Jayesh S
authors: JS
authors: Salvi
authors: Department of Biochemistry and Donnelly Centre, University of Toronto, 160 College Street, Toronto, ON M5S 3E1, Canada.
authors: Brandon
authors: B
authors: Ho
authors: Department of Laboratory Medicine and Pathobiology, Faculty of Medicine, University of Toronto, 1 King's College Circle, Toronto, ON M5S 1A8, Canada.
authors: Amanda
authors: A
authors: Hall
authors: Department of Laboratory Medicine and Pathobiology, Faculty of Medicine, University of Toronto, 1 King's College Circle, Toronto, ON M5S 1A8, Canada.
authors: Elva
authors: E
authors: Vidya
authors: Department of Laboratory Medicine and Pathobiology, Faculty of Medicine, University of Toronto, 1 King's College Circle, Toronto, ON M5S 1A8, Canada.
authors: Ru
authors: R
authors: Guo
authors: Department of Laboratory Medicine and Pathobiology, Faculty of Medicine, University of Toronto, 1 King's College Circle, Toronto, ON M5S 1A8, Canada.
authors: Samuel A
authors: SA
authors: Killackey
authors: Department of Laboratory Medicine and Pathobiology, Faculty of Medicine, University of Toronto, 1 King's College Circle, Toronto, ON M5S 1A8, Canada.
authors: Nancy
authors: N
authors: Liu
authors: Department of Laboratory Medicine and Pathobiology, Faculty of Medicine, University of Toronto, 1 King's College Circle, Toronto, ON M5S 1A8, Canada Canada Research Chairs Program, Faculty of Medicine, University of Toronto, 1 King's College Circle, Toronto, ON M5S 1A8, Canada.
authors: Jeffrey E
authors: JE
authors: Lee
authors: Department of Biochemistry and Donnelly Centre, University of Toronto, 160 College Street, Toronto, ON M5S 3E1, Canada.
authors: Grant W
authors: GW
authors: Brown
authors: Department of Laboratory Medicine and Pathobiology, Faculty of Medicine, University of Toronto, 1 King's College Circle, Toronto, ON M5S 1A8, Canada Canada Research Chairs Program, Faculty of Medicine, University of Toronto, 1 King's College Circle, Toronto, ON M5S 1A8, Canada karim.mekhail@utoronto.ca.
authors: Karim
authors: K
authors: Mekhail
mesh_terms: D031204:Caloric Restriction; D002460:Cell Line; D004247:DNA / Q000235:genetics* / Q000378:metabolism*; D042822:Genomic Instability; D006801:Humans; D008274:Magnesium / Q000378:metabolism*; D012313:RNA / Q000235:genetics* / Q000378:metabolism*; D015003:Yeasts / Q000235:genetics / Q000378:metabolism
chemical_list: D012313:RNA; D004247:DNA; D008274:Magnesium