Mass spectrometry-based proteomics and other technologies have matured to enable routine acquisition of system-wide data sets that describe concentrations, modifications, and interactions of proteins, mRNAs, and other molecules. Productive integrative studies differ from parallel data analysis by quantitative modeling of the relationships between data. We outline steps and considerations towards integromic studies to exploit the synergy between data sets.
Germ cells undergoing meiosis rely on an intricate network of surveillance mechanisms that govern the production of euploid gametes for successful sexual reproduction. These surveillance mechanisms are particularly crucial during meiotic prophase, when cells execute a highly orchestrated program of chromosome morphogenesis and recombination, which must be integrated with the meiotic cell division machinery to ensure the safe execution of meiosis. Dynamic protein phosphorylation, controlled by kinases and phosphatases, has emerged as one of the main signaling routes for providing readout and regulation of chromosomal and cellular behavior throughout meiotic prophase. In this review, we discuss common principles and provide detailed examples of how these phosphorylation events are employed to ensure faithful passage of chromosomes from one generation to the next.
Meiotic cells introduce a numerous programmed DNA breaks into their genome to stimulate meiotic recombination and ensure controlled chromosome inheritance and fertility. A checkpoint network involving key kinases and phosphatases coordinates the repair of these DNA breaks, but the precise phosphorylation targets remain poorly understood. It is also unknown whether meiotic DNA breaks change gene expression akin to the canonical DNA-damage response. To address these questions, we analyzed the meiotic DNA break response in Saccharomyces cerevisiae using multiple systems-level approaches. We identified 332 DNA break–dependent phosphorylation sites, vastly expanding the number of known events during meiotic prophase. Less than half of these events occurred in recognition motifs for the known meiotic checkpoint kinases Mec1 (ATR), Tel1 (ATM), and Mek1 (CHK2), suggesting that additional kinases contribute to the meiotic DNA-break response. We detected a clear transcriptional program but detected only very few changes in protein levels. We attribute this dichotomy to a decrease in transcript levels after meiotic entry that dampens the effects of break-induced transcription sufficiently to cause only minimal changes in the meiotic proteome.
Meiotic cells introduce a large number of programmed DNA breaks into their genome to stimulate meiotic recombination and ensure controlled chromosome inheritance and fertility. An intricate checkpoint network involving key kinases and phosphatases coordinates the repair of these DNA breaks during meiosis, but the precise DNA break-dependent phosphorylation targets remain poorly understood. It is also unknown whether meiotic DNA breaks change gene expression akin to the canonical DNA-damage response. To address these questions, we analyzed the meiotic DNA break response in Saccharomyces cerevisiae using multiple systems-level approaches. We identified 332 DNA break-dependent phosphorylation sites, vastly expanding the number of known DNA break-dependent phosphorylation events during meiotic prophase. Only about half of these events occurred in recognition motifs for the known meiotic checkpoint kinases Mec1 (ATR), Tel1 (ATM) and Mek1 (CHK2), suggesting that additional kinases contribute to the meiotic DNA break response. Surprisingly, the numerous changes in phosphorylation were accompanied by very few changes in protein levels despite a clearly detectable transcriptional response. To explain this dichotomy, we show that meiotic entry lowers the expression baseline of many mRNAs enough so that subsequent break-dependent mRNA production has no measurable effects on the largely stable proteome.
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