The SMC-5/6 Complex and the HIM-6 (BLM) Helicase Synergistically Promote Meiotic Recombination Intermediate Processing and Chromosome Maturation during Caenorhabditis elegans Meiosis

Abstract

Meiotic recombination is essential for the repair of programmed double strand breaks (DSBs) to generate crossovers (COs) during meiosis. The efficient processing of meiotic recombination intermediates not only needs various resolvases but also requires proper meiotic chromosome structure. The Smc5/6 complex belongs to the structural maintenance of chromosome (SMC) family and is closely related to cohesin and condensin. Although the Smc5/6 complex has been implicated in the processing of recombination intermediates during meiosis, it is not known how Smc5/6 controls meiotic DSB repair. Here, using Caenorhabditis elegans we show that the SMC-5/6 complex acts synergistically with HIM-6, an ortholog of the human Bloom syndrome helicase (BLM) during meiotic recombination. The concerted action of the SMC-5/6 complex and HIM-6 is important for processing recombination intermediates, CO regulation and bivalent maturation. Careful examination of meiotic chromosomal morphology reveals an accumulation of inter-chromosomal bridges in smc-5; him-6 double mutants, leading to compromised chromosome segregation during meiotic cell divisions. Interestingly, we found that the lethality of smc-5; him-6 can be rescued by loss of the conserved BRCA1 ortholog BRC-1. Furthermore, the combined deletion of smc-5 and him-6 leads to an irregular distribution of condensin and to chromosome decondensation defects reminiscent of condensin depletion. Lethality conferred by condensin depletion can also be rescued by BRC-1 depletion. Our results suggest that SMC-5/6 and HIM-6 can synergistically regulate recombination intermediate metabolism and suppress ectopic recombination by controlling chromosome architecture during meiosis.

SMC5/6 is required for the formation of segregation-competent bivalent chromosomes during meiosis I in mouse oocytes

“…SMC5/6 was also visible along chromosome axes at pachynema in oocytes, which was also detected in mouse spermatocytes (Gomez et al, 2013). In addition, transient foci of SMC6 were detected along the chromosome arms in female germ cells during pachynema, suggesting a role during meiotic recombination, which has previously been reported using budding yeast and Caenorhabditis elegans (Bickel et al, 2010;Hong et al, 2016;Checchi et al, 2014;Copsey et al, 2013;Lilienthal et al, 2013;Xaver et al, 2013). In mammals, every chromosome pair obtains many recombination sites but generally yields only one to two crossover sites (Kauppi et al, 2004).…”

“…Abnormal condensin localization was also observed using Smc5 cKO mouse embryonic stem cells (Pryzhkova and Jordan, 2016). Furthermore, mutation of smc-5 in C. elegans leads to abnormal distribution of condensin along bivalents during meiosis I (Hong et al, 2016). However, previous studies were not able to determine whether the defects in condensin localization were specific to the prophase to metaphase transition.…”

Non-SMC Element 2 (NSMCE2) of the SMC5/6 Complex Helps to Resolve Topological Stress

“…SMC5/6 seems to be involved in double-strand break (DSB) repair as it is enriched at DSB sites in budding yeast and C. elegans [12,14,16]; it localizes side by side with RAD51 in budding yeast and humans [9,12,16] and its deletion results in an increase in RAD51 foci and chromosome fragmentation in C. elegans [14]. Furthermore, Smc5/6 has been found to play a role in the resolution of meiotic recombination intermediates and mutations of Smc5, Smc6 or the SUMO ligase domain of Nse2 lead to the accumulation of toxic joint molecules in yeast and C. elegans [12,15,16,19,20,21,22]. …”

C. elegans BRC-1-BRD-1 functions at an early step of DSB processing and inhibits supernumerary crossovers during male meiosis

“…Alteration in crossover distribution in the brc-1 mutant may result from changes in the chromatin landscape, which has been linked to BRCA1 function in mammals (BROERING et al 2014;DENSHAM et al 2016), and has been shown to alter crossover patterning (MEZARD et al 2015;YU et al 2016). A surprising number of C. elegans meiotic mutants display altered crossover distribution (ZETKA AND ROSE 1995;MENEELY et al 2012;SAITO et al 2012;SAITO et al 2013;WAGNER et al 2010;CHUNG et al 2015;HONG et al 2016;JAGUT et al 2016;Janisiw et al 2020). While the underlying mechanisms are not clear, it may be a consequence of altering the use of crossover versus non-crossover pathways within a particular chromatin environment as suggested by Saito and Colaiacovo (SAITO AND COLAIACOVO 2017).…”