Structural Maintenance of Chromosomes (SMC) Proteins Promote Homolog-Independent Recombination Repair in Meiosis Crucial for Germ Cell Genomic Stability

Abstract

In meiosis, programmed DNA breaks repaired by homologous recombination (HR) can be processed into inter-homolog crossovers that promote the accurate segregation of chromosomes. In general, more programmed DNA double-strand breaks (DSBs) are formed than the number of inter-homolog crossovers, and the excess DSBs must be repaired to maintain genomic stability. Sister-chromatid (inter-sister) recombination is postulated to be important for the completion of meiotic DSB repair. However, this hypothesis is difficult to test because of limited experimental means to disrupt inter-sister and not inter-homolog HR in meiosis. We find that the conserved Structural Maintenance of Chromosomes (SMC) 5 and 6 proteins in Caenorhabditis elegans are required for the successful completion of meiotic homologous recombination repair, yet they appeared to be dispensable for accurate chromosome segregation in meiosis. Mutations in the smc-5 and smc-6 genes induced chromosome fragments and dismorphology. Chromosome fragments associated with HR defects have only been reported in mutants, which have disrupted inter-homolog crossover. Surprisingly, the smc-5 and smc-6 mutations did not disrupt the formation of chiasmata, the cytologically visible linkages between homologous chromosomes formed from meiotic inter-homolog crossovers. The mutant fragmentation defect appeared to be preferentially enhanced by the disruptions of inter-homolog recombination but not by the disruptions of inter-sister recombination. Based on these findings, we propose that the C. elegans SMC-5/6 proteins are required in meiosis for the processing of homolog-independent, presumably sister-chromatid-mediated, recombination repair. Together, these results demonstrate that the successful completion of homolog-independent recombination is crucial for germ cell genomic stability.

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).…”

Increased Meiotic Crossovers and Reduced Genome Stability in Absence of Schizosaccharomyces pombe Rad16 (XPF)

“…We see little additive effect in rad16-249 rad57Δ double mutants. Thus we suggest that Rad16 may play a role in resolution of events mediated by Rad55/57, particularly those involving the sister.Consistent with this, mutations that reduce sister chromatid exchanges in C. elegans without affecting crossovers between homologs generate DNA fragments (Bickel et al 2010), leading to the suggestion that homolog-independent recombination is important to preserve genome stability in meiosis. We conclude that events involving the sister chromatid, rather than the homologous chromosome, are similarly important for meiotic genome stability in fission yeast.…”

Germ Cell Apoptosis and DNA Damage Responses

“…During meiosis, HR is a more tricky undertaking. Meiotic cells must differentiate between the homologous chromosome as a template to facilitate homologous meiotic recombination, as opposed to using the sister chromatid to facilitate DNA double-strand break repair (Couteau and Zetka 2011 ;Bickel et al 2010 ;Adamo et al 2008 ) . The two related protein kinases ATM and ATR are critically important regulators of DNA damage responses in cells.…”

“…The former mode of HR is required for meiotic cross-over recombination and gene conversion. Both C. elegans brc-1, the worm homolog of the mammalian breast and ovarian cancer susceptibility gene BRCA1, and the structural maintenance of chromosomes (SMC) proteins SMC-5 and SMC-6 were shown to be speci fi cally required for meiotic sister-chromatid recombination (Bickel et al 2010 ;Adamo et al 2008 ) . In the corresponding mutants, no overt defect in meiotic cross-over recombination can be observed and chiasmata occur as in wild type.…”