title: Polymerase epsilon is required to maintain replicative senescence.
abstract: Replicative senescence is a permanent cell cycle arrest in response to extensive telomere shortening. To understand the mechanisms behind a permanent arrest, we screened for factors affecting replicative senescence in budding yeast lacking telomere elongation pathways. Intriguingly, we found that DNA polymerase epsilon (Pol ε) acts synergistically with Exo1 nuclease to maintain replicative senescence. In contrast, the Pol ε-associated checkpoint and replication protein Mrc1 facilitates escape from senescence. To understand this paradox, in which DNA-synthesizing factors cooperate with DNA-degrading factors to maintain arrest, whereas a checkpoint protein opposes arrest, we analyzed the dynamics of double- and single-stranded DNA (ssDNA) at chromosome ends during senescence. We found evidence for cycles of DNA resection, followed by resynthesis. We propose that resection of the shortest telomere, activating a Rad24(Rad17)-dependent checkpoint pathway, alternates in time with an Mrc1-regulated Pol ε resynthesis of a short, double-stranded chromosome end, which in turn activates a Rad9(53BP1)-dependent checkpoint pathway. Therefore, instead of one type of DNA damage, different types (ssDNA and a double-strand break-like structure) alternate in a "vicious circle," each activating a different checkpoint sensor. Every time resection and resynthesis switches, a fresh signal initiates, thus preventing checkpoint adaptation and ensuring the permanent character of senescence.
authors.affiliation: Institute for Ageing and Health, Institute of Human Genetics, Centre for Life, Newcastle upon Tyne NE1 3BZ, United Kingdom.
authors.forename: Abhyuday M
authors.initials: AM
authors.lastname: Deshpande
authors.forename: Iglika G
authors.initials: IG
authors.lastname: Ivanova
authors.forename: Vasil
authors.initials: V
authors.lastname: Raykov
authors.forename: Yuan
authors.initials: Y
authors.lastname: Xue
authors.forename: Laura
authors.initials: L
authors.lastname: Maringele
mesh_terms: D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism; D004257:DNA Polymerase II / Q000378:metabolism*; D004261:DNA Replication; D004271:DNA, Fungal / Q000378:metabolism*; D004277:DNA, Single-Stranded / Q000096:biosynthesis; D012441:Saccharomyces cerevisiae / Q000201:enzymology*
chemical_list: D018797:Cell Cycle Proteins; D004271:DNA, Fungal; D004277:DNA, Single-Stranded; C069930:rad9 protein; D004257:DNA Polymerase II