Cisplatin-induced DNA double-strand breaks promote meiotic chromosome synapsis in PRDM9-controlled mouse hybrid sterility.

Liu Wang,Jiri Forejt,Barbora Valiskova

doi:10.7554/elife.42511

Abstract

PR domain containing 9 (Prdm9) is specifying hotspots of meiotic recombination but in hybrids between two mouse subspecies Prdm9 controls failure of meiotic chromosome synapsis and hybrid male sterility. We have previously reported that Prdm9-controlled asynapsis and meiotic arrest are conditioned by the inter-subspecific heterozygosity of the hybrid genome and we presumed that the insufficient number of properly repaired PRDM9-dependent DNA double-strand breaks (DSBs) causes asynapsis of chromosomes and meiotic arrest (Gregorova et al., 2018). We now extend the evidence for the lack of properly processed DSBs by improving meiotic chromosome synapsis with exogenous DSBs. A single injection of chemotherapeutic drug cisplatin increased frequency of RPA and DMC1 foci at the zygotene stage of sterile hybrids, enhanced homolog recognition and increased the proportion of spermatocytes with fully synapsed homologs at pachytene. The results bring a new evidence for a DSB-dependent mechanism of synapsis failure and infertility of intersubspecific hybrids.

Highlights

Proper synapsis of homologous chromosomes is an important meiotic checkpoint preventing germline transfer of harmful genic and chromosomal mutations to the generations (Schimenti, 2005; Zickler and Kleckner, 2015; Rinaldi et al, 2017)
Synapsis of homologous chromosomes is initiated at the leptotene stage of the first meiotic prophase by induction of developmentally programmed, SPO11-induced DNA double-strand breaks (DSBs) (Keeney et al, 1997; Keeney et al, 1999; Romanienko and Camerini-Otero, 2000)
We report that the exogenous DSBs generated by chemotherapeutic drug cisplatin (Basu and Krishnamurthy, 2010) enhanced meiotic synapsis of homologous chromosomes in sterile mouse inter-subspecies hybrids, bringing independent evidence on the mechanism of meiotic chromosome asynapsis (Gregorova et al, 2018) and supporting the ’asymmetry’ hypothesis (Davies et al, 2016)

Summary

Introduction

Proper synapsis of homologous chromosomes is an important meiotic checkpoint preventing germline transfer of harmful genic and chromosomal mutations to the generations (Schimenti, 2005; Zickler and Kleckner, 2015; Rinaldi et al, 2017).

Results

Conclusion