Shu complex SWS1-SWSAP1 promotes early steps in mouse meiotic recombination

Carla M Abreu,Rohit Prakash,Peter J Romanienko,Ignasi Roig,Maria Jasin,Scott Keeney

doi:10.1038/s41467-018-06384-x

Abstract

The DNA-damage repair pathway homologous recombination (HR) requires factors that promote the activity of strand-exchange protein RAD51 and its meiosis-specific homolog DMC1. Here we show that the Shu complex SWS1-SWSAP1, a candidate for one such HR regulator, is dispensable for mouse viability but essential for male and female fertility, promoting the assembly of RAD51 and DMC1 on early meiotic HR intermediates. Only a fraction of mutant meiocytes progress to form crossovers, which are crucial for chromosome segregation, demonstrating crossover homeostasis. Remarkably, loss of the DNA damage checkpoint kinase CHK2 rescues fertility in females without rescuing crossover numbers. Concomitant loss of the BRCA2 C terminus aggravates the meiotic defects in Swsap1 mutant spermatocytes, suggesting an overlapping role with the Shu complex during meiotic HR. These results demonstrate an essential role for SWS1-SWSAP1 in meiotic progression and emphasize the complex interplay of factors that ensure recombinase function.

Highlights

The DNA-damage repair pathway homologous recombination (HR) requires factors that promote the activity of strand-exchange protein RAD51 and its meiosis-specific homolog DMC1
SWSAP1 was identified in human cells through its association with SWS1; it is considered to be a novel RAD51 paralog, since like RAD51 and the canonical RAD51 paralogs, it contains Walker A and B motifs which are involved in nucleotide binding/hydrolysis[11]
Concomitant loss of a BRCA2 domain that stabilizes RAD51 filaments leads to an even greater severity in meiotic defects than seen in Shu mutants. These results demonstrate the critical role the Shu complex plays in mammalian meiosis, which can be ameliorated by loss of a DNA damage signaling protein (CHK2) or worsened by loss of a BRCA2 domain

Summary

Introduction

The DNA-damage repair pathway homologous recombination (HR) requires factors that promote the activity of strand-exchange protein RAD51 and its meiosis-specific homolog DMC1. Unlike SWS1, SWS1-associated proteins are highly diverse in their structure and number in different organisms (i.e., budding yeast, Shu[1], Psy[3], Csm[2]; fission yeast Rdl[1], Rlp[1]; worm, RIP-1, and RFS-1)[10,11,14,15,16,17,18,19] These proteins are considered to be RAD51 paralogs, but only some appear to be capable of nucleotide binding/hydrolysis (i.e., human SWSAP1 and worm RFS-1)[11,19], while others are truncated and/or lack the critical Walker motifs[20]. Concomitant loss of a BRCA2 domain that stabilizes RAD51 filaments leads to an even greater severity in meiotic defects than seen in Shu mutants These results demonstrate the critical role the Shu complex plays in mammalian meiosis, which can be ameliorated by loss of a DNA damage signaling protein (CHK2) or worsened by loss of a BRCA2 domain (the C terminus)

Methods

Results

Conclusion