Reflections on the early days of the DNA damage response pathway in eukaryotes

Abstract The DNA damage response (DDR) pathway has emerged as the central signaling network that preserves genome stability by using sensors to monitor the genome for aberrant structures and establishing signaling centers that promote organismal homeostasis. This review revisits the formative years of DDR research, focusing on the genetic dissection of the pathway in Saccharomyces cerevisiae and its evolution into a broadly conserved eukaryotic signaling system. Early studies of ribonucleotide reductase regulation, replication stress–induced transcription, and cell cycle control identified key regulators, including MEC1, DDC2, TEL1, MRC1, RAD53, DUN1, and RAD9, providing the first evidence that DNA damage signaling is propagated through a protein kinase cascade. This cascade is initiated when RPA binds to ssDNA generated by replication blocks and double-strand DNA breaks, thereby activating the apical MEC1/ATR kinase. These discoveries integrate the contemporaneous cell cycle checkpoint literature into a more comprehensive framework in which the DDR coordinates replication fork stability, replication origin firing, nucleotide metabolism, DNA repair, genome maintenance, and cell cycle control to maintain genomic stability. Parallel studies in Schizosaccharomyces pombe, Xenopus, and mammalian systems revealed the remarkable evolutionary conservation of the pathway and linked DDR dysfunction to a wide spectrum of human diseases, including cancer. In retrospect, the emergence of the DDR field highlights the extraordinary power of classical genetics combined with molecular biology to uncover a complex signaling network that now occupies a central position in chromosome biology, cancer research, aging, immunity, and therapeutic responses.