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A chromatin-associated protein required for inducing and limiting meiotic DNA double-strand break formation
1Department of Chromosome Biology, Max F. Perutz Laboratories, University of Vienna, 1030 Vienna, Austria.
Abstract:
Programmed DNA double-strand breaks (DSBs) are required for meiotic recombination, but the number is strictly controlled because they are potentially harmful. Here we report a novel protein, Pars11, which is required for Spo11-dependent DSB formation in the protist Tetrahymena. Pars11 localizes to chromatin early in meiotic prophase in a Spo11-independent manner and is removed before the end of prophase. Pars11 removal depends on DSB formation and ATR-dependent phosphorylation. In the absence of the DNA damage sensor kinase ATR, Pars11 is retained on chromatin and excess DSBs are generated. Similar levels of Pars11 persistence and DSB overproduction occur in a non-phosphorylatable pars11 mutant. We conclude that Pars11 supports DSB formation by Spo11 until enough DSBs are formed; thereafter, DSB production stops in response to ATR-dependent degradation of Pars11 or its removal from chromatin. A similar DSB control mechanism involving a Rec114-Tel1/ATM-dependent negative feedback loop regulates DSB formation in budding yeast. However, there is no detectable sequence homology between Pars11 and Rec114, and DSB numbers are more tightly controlled by Pars11 than by Rec114. The discovery of this mechanism for DSB regulation in the evolutionarily distant protist and fungal lineages suggests that it is conserved across eukaryotes.
Insights
A novel protein, Pars11, regulates DNA double-strand break (DSB) formation during meiosis. Its removal, dependent on DSB formation and ATR kinase, prevents excess harmful DSBs, suggesting a conserved eukaryotic mechanism.
Area of Science:
- Molecular Biology
- Genetics
- Cell Biology
Background:
- Programmed DNA double-strand breaks (DSBs) are essential for meiotic recombination but must be tightly controlled due to their potential for DNA damage.
- Understanding the mechanisms that regulate DSB formation is crucial for comprehending genome stability during sexual reproduction.
Purpose of the Study:
- To identify and characterize novel proteins involved in the regulation of meiotic DSB formation.
- To elucidate the molecular mechanism by which DSB numbers are controlled during meiosis in the protist Tetrahymena.
Main Methods:
- Chromatin immunoprecipitation to determine Pars11 localization.
- Analysis of DSB formation in wild-type and mutant strains lacking key regulatory proteins (e.g., ATR).
- Biochemical assays to assess protein phosphorylation and degradation.
Main Results:
- A novel protein, Pars11, was identified and shown to be essential for Spo11-dependent DSB formation in Tetrahymena.
- Pars11 localizes to chromatin early in meiotic prophase and is removed via ATR-dependent phosphorylation and DSB formation.
- Inactivation of ATR or a non-phosphorylatable Pars11 mutant leads to Pars11 persistence on chromatin and overproduction of DSBs.
Conclusions:
- Pars11 acts as a positive regulator of DSB formation, supporting Spo11 activity until sufficient DSBs are generated.
- ATR-dependent removal of Pars11 functions as a negative feedback mechanism to limit DSB formation, preventing harmful excess.
- This DSB regulatory mechanism involving Pars11 in protists shares functional similarities with, yet is distinct from, the Rec114-Tel1/ATM pathway in yeast, indicating a conserved eukaryotic regulatory principle.
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