This Fleming Lecture reviews DNA structure checkpoint pathways in the fission yeast Schizosaccharomyces pombe, which monitor DNA status and regulate cell cycle progression. Two overlapping checkpoint pathways have been identified: the DNA damage checkpoint that arrests mitosis when DNA is damaged, and the DNA replication checkpoint that prevents mitosis during DNA replication problems. Both pathways require a core complex of at least six checkpoint proteins (Rad1, Rad3, Rad9, Rad17, Rad24, and Hus1) that sense DNA structural changes and activate downstream kinases Chk1 and Cds1. These kinases signal to mitotic and replication machinery, coordinating repair, mitosis, and replication. The Chk1 kinase responds to DNA damage outside S phase, while Cds1 is activated during S phase and also responds to stalled replication. The checkpoint proteins have been conserved throughout eukaryotes, with human homologues (ATM, ATR, and Chk1) playing roles in DNA damage responses and meiotic recombination. This research establishes a fundamental model for understanding how cells protect genomic integrity through checkpoint control mechanisms.

Key findings

• Two distinct checkpoint pathways in S. pombe monitor DNA damage and replication status, converging on a common set of six core Rad proteins that form a 'guardian complex' to detect DNA structure changes
• Downstream kinases Chk1 and Cds1 transduce checkpoint signals differently depending on cell cycle phase: Chk1 responds to DNA damage outside S phase, while Cds1 is specifically activated during S phase and by replication fork stalling
• Checkpoint proteins coordinate multiple DNA responses beyond mitotic arrest, including transcriptional activation of repair genes, replication arrest, and homologous recombination-dependent survival of DNA damage during S phase
• Checkpoint pathway components are structurally and functionally conserved in mammalian cells, with human ATM and ATR kinases analogous to S. pombe Rad3, and human Chk1 showing similar phosphorylation-based regulation of Cdc25