Nitrogen starvation reveals the mitotic potential of mutants in the S/MAPK pathways

Abstract

The genetics of quiescence is an emerging field compared to that of growth, yet both states generate spontaneous mutations and genetic diversity fueling evolution. Reconciling mutation rates in dividing conditions and mutation accumulation as a function of time in non-dividing situations remains a challenge. Nitrogen-starved fission yeast cells reversibly arrest proliferation, are metabolically active and highly resistant to a variety of stresses. Here, we show that mutations in stress-and mitogen-activated protein kinase (S/MAPK) signaling pathways are enriched in aging cultures. Targeted resequencing and competition experiments indicate that these mutants arise in the first month of quiescence and expand clonally during the second month at the expense of the parental population. Reconstitution experiments show that S/MAPK modules mediate the sacrifice of many cells for the benefit of some mutants. These findings suggest that non-dividing conditions promote genetic diversity to generate a social cellular environment prone to kin selection.

Barcode Sequencing and a High-throughput Assay for Chronological Lifespan Uncover Ageing-associated Genes in Fission Yeast

“…These results suggest that the persistence of these mutants at late timepoints reflects factors unrelated to longevity. For example, the nutrients released from dying mutants might be scavenged and provide a survival advantage to certain other mutants in a heterogeneous cell culture, a phenomenon that has been described in bacteria [40, 41], and recently in S. pombe cells during quiescence [42]. We conclude that samples from very late timepoints are also biased by biological phenomena that do not reflect longevity.…”

R-loops and regulatory changes in chronologically ageing fission yeast cells drive non-random patterns of genome rearrangements

“…Chronological lifespan is defined as the time a cell survives in a quiescent, non-dividing state, which models post-mitotic ageing of somatic metazoan cells [21,33]. Quiescent S. pombe cells feature distinct DNA-damage responses [28,38,39] and distinct mutational forces that can promote genetic diversity [26,27]. Here we interrogate aberrant genomic DNA-junction sequences in non-dividing S. pombe cells, revealing unique signatures of ageing-associated chromosomal rearrangements and suggesting their mechanistic underpinning.…”

“…Impaired NHEJ leads to accelerated ageing in human patients and mouse models, and MMEJ increases with age [23]. Genome re-sequencing studies during ageing have been limited to mitochondrial DNA [24,25], small genetic variants [26,27] and duplications [28], or proliferating cells [29]. No systematic approaches have been applied to identify heterogeneous, rare chromosomal rearrangements in non-dividing, somatic cells [15,[30][31][32].…”

R-loops and regulatory changes in chronologically ageing fission yeast cells drive non-random patterns of genome rearrangements

“…Genome re-sequencing studies during ageing have been limited to mitochondrial DNA (Williams et al 2013;Kennedy et al 2013), small genetic variants (Gangloff et al 2017;Makarenko et al 2020) and duplications (Maestroni et al 2017), or proliferating cells (Hu et al 2014). No systematic approaches have been applied to identify heterogeneous, rare chromosomal rearrangements in non-dividing, somatic cells (Quispe-Tintaya et al 2016;White and Vijg 2016;Laurie et al 2012;Jacobs et al 2012).…”

“…Chronological lifespan is defined as the time a cell survives in a quiescent, nondividing state, which models post-mitotic ageing of somatic metazoan cells (López-Otín et al 2013;Kaeberlein 2010). Quiescent S. pombe cells feature distinct DNA-damage responses (Mochida and Yanagida 2006;Ferreira and Cooper 2004;Maestroni et al 2017) and distinct mutational forces that can promote genetic diversity (Makarenko et al 2020;Gangloff et al 2017). Here we interrogate aberrant genomic DNA-junction sequences in non-dividing S. pombe cells, revealing distinct signatures of ageing-associated chromosomal rearrangements and suggesting their mechanistic underpinning.…”