DS0405 -

Control mechanism of meiotic DSB interference and impact on genome stability – MeioInt

Submission summary

DNA double stand breaks (DSBs) are among the most harmful DNA lesions since a single unrepaired DNA break is enough to trigger cell death. Depending on the cell cycle stage, DSBs can be repaired by non homologous end joining (NHEJ) or by homologous recombination (HR), and dysfunction of any of these two pathways leads to genome instability and can result in severe diseases in human. While most DSBs occur accidentally, DSBs are also part of cellular programs that shuffle the genetic information such as VDJ recombination and meiosis. It is therefore expected that both the formation and repair of programmed DSBs are tightly controlled to prevent genomic instability. While much is known about DSB repair, much less is known about the regulation of the formation of programmed DSBs, notably meiotic DSBs, which constitutes the focus of our project.

During meiosis, the topoisomerase-like protein Spo11 generates DSBs to promote crossover (CO) recombination between homologous chromosomes, which in turn ensures accurate chromosome segregation and genetic diversity. Importantly, Spo11 cleaves at hotspots that are largely determined by epigenetic marks. Using the budding yeast Saccharomyces cerevisiae as a model, we recently discovered that meiotic DSBs display distance-dependent inter-hotspots interference in cis, in which the occurrence of a DSB within a hotspot suppresses DSB formation within adjacent hotspots. We showed that DSB interference, likely conserved in mammals, is mediated by the yeast protein kinase ATM orthologue Tel1: upon ablation of Tel1 function, meiotic DSBs arise in proximity to one another on the same chromatid, and clusters of DSBs colocalize within chromatin loops.

The aim of this MeioInt project is to understand the mechanism of Tel1-dependent meiotic DSB control and its functional impact on meiotic recombination and genome integrity. To do so, we will combine complementary molecular genetics, genomics and proteomics approaches with compelling preliminary results to test different working models about the dynamics, partners and targets of Tel1 at meiotic DSBs. Notably, our preliminary results support a non-catalytic role of Tel1 in the control of inter-hotspot DSB interference, and a Tel1 catalytic role for local, intra-hotspot DSB interference. This result was unexpected since despite intense scrutiny no clear evidence for a non-catalytic role of Tel1/ATM had emerged in the literature and studies had overwhelmingly been focusing on its kinase dependent function. Finally, the defect in the control of meiotic DSB distribution observed in a yeast tel1 mutant is reminiscent of the aberrant RAG-induced DNA breaks in atm deficient lymphocytes and suggests a common Tel1/ATM-dependent DSB control mechanism, the details of which have yet to be worked out.

Overall, this project involves a combination of classical and cutting edge genome-wide technologies, most of them being already handled by this consortium. BL lab has first hand experience with genome wide genotyping of meiotic progeny. MN lab handles the analysis of Spo11 bound DNA and subsequent genome-wide mapping. Ultimately, MeioInt is a fundamental research project that will shed light on the mechanism of Tel1/ATM-mediated DSB interference in meiotic cells and its contribution to germline genome instability, matters at the intersection of fundamental genetics, medicine and biotechnology, and therefore has a strong societal impact.

Project coordination

Bertrand LLORENTE (Centre National de la Recherche Scientifique délégation Provence et Corse _CRCM UMR7258)

The author of this summary is the project coordinator, who is responsible for the content of this summary. The ANR declines any responsibility as for its contents.

Partner

CNRS DR12 _ CRCM UMR7258 Centre National de la Recherche Scientifique délégation Provence et Corse _CRCM UMR7258
MJN MRC Genome Damage and Stability Centre

Help of the ANR 284,413 euros
Beginning and duration of the scientific project: - 36 Months

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