TRIP13 fosters both transcriptional silencing and DSB repair during meiosis

Abstract

During meiosis, the coordinated suppression of global gene transcription and induction of double-strand breaks (DSBs) genome wide is crucial for successful gamete formation. The AAA+ ATPase TRIP13 is a master meiotic regulator involved in numerous cellular processes, including DSB repair, organization of the meiotic chromosome axis, and meiotic silencing of unsynapsed axes. Here, we examine the involvement of TRIP13 in transcription suppression and DSB repair during meiotic prophase I in mice. Because TRIP13 is required for silencing of sex chromosomes at pachynema, we hypothesized that it may also be involved in the global transcription suppression that begins at the onset of meiotic prophase. Indeed, as predicted, we observed increased incorporation of 5-ethynyl uridine in early stages of meiotic prophase I and a higher presence of the active form of RNA polymerase II in Trip13 mutant spermatocytes. RNA sequencing data revealed that more than two-thirds of upregulated transcripts came from the sex chromosomes. Given this more general role in transcription silencing, we also tested whether TRIP13 promotes the transcription block that causes meiotic arrest in synapsis-deficient oocytes. However, Trip13 ablation did not rescue Spo11-/- oocytes, which experience asynapsis without DSB repair defects. Instead, Trip13 mutation did increase the number of oocytes in Dmc1-/- Chk2-/- mice, in which DSBs persist unrepaired. This rescue seems attributable to a previously unknown function of TRIP13 in preventing DSB repair by non-canonical pathways, as we observed fewer homologous recombination markers along with an increased presence of non-homologous end joining markers in the triple mutant cells. These findings underscore TRIP13s multifaceted role in transcription and DSB repair regulation during meiosis, highlighting its importance and potential for further meiotic regulation and fertility research.