Biology subjects

Kearsey, S. E.

Publications and source records attributed to Kearsey, S. E..

2 recordsLinked to original sources

bioRxiv2024

Cytoplasmic localization of ribonucleotide reductase is essential for genome stability

Ribonucleotide reductase (RNR) is a major determinant of dNTP concentrations and its correct regulation is crucial for genome stability. Active RNR is cytoplasmic but the significance of this localization, away from DNA synthesis, is unclear, particularly as RNR is targeted to the nucleus after DNA damage occurs. We subverted the localization of fission yeast RNR by tagging the large (Cdc22R1) and small (Suc22R2) subunits with nuclear localization signal sequences. Directing RNR to the nucleus caused a slow S-phase and increased mutagenesis, in spite of predicted constitutive activation of RNR. Defective function of nuclear RNR is also suggested by the formation of Cdc22R1 supramolecular filaments and defective RNR reoxidation. In contrast, constitutively nuclear Cdc22 or Suc22 has little effect on DNA damage repair and in fact suppresses rad3{Delta}-sensitivity to DNA damaging agents. We suggest that there is an inadequate flux of substrate through nuclear RNR for S phase, but nuclear targeting of RNR may facilitate DNA damage repair under some circumstances.

cell biology↗

bioRxiv2020

Persistent broken chromosome inheritance drives genome instability

Persistent DNA damage arising from unrepaired broken chromosomes or telomere loss can promote DNA damage checkpoint adaptation, and cell cycle progression, thereby increasing cell survival but also genome instability. However, the nature and extent of such instability is unclear. We show, using Schizosaccharomyces pombe, that inherited broken chromosomes, arising from failed homologous recombination repair, are subject to cycles of segregation, DNA replication and extensive end-processing, termed here SERPent cycles, by daughter cells, over multiple generations. Following Chk1 loss these post-adaptive cycles continue until extensive processing through inverted repeats promotes annealing, fold-back inversion and a spectrum of chromosomal rearrangements, typically isochromosomes, or chromosome loss, in the resultant population. These findings explain how persistent DNA damage drives widespread genome instability, with implications for punctuated evolution, genetic disease and tumorigenesis. One Sentence SummaryReplication and processing of inherited broken chromosomes drives chromosomal instability.

molecular biology↗