Chromosome-autonomous feedback down-regulates meiotic DNA break competence upon synaptonemal complex formation

Abstract

The number of DNA double-strand breaks (DSBs) initiating meiotic recombination is elevated in Saccharomyces cerevisiae mutants that are globally defective in forming crossovers and synaptonemal complex (SC), a protein scaffold juxtaposing homologous chromosomes. These mutants thus appear to lack a negative feedback loop that inhibits DSB formation when homologs engage one another. This feedback is predicted to be chromosome autonomous, but this has not been tested. Moreover, what chromosomal process is recognized as “homolog engagement” remains unclear. To address these questions, we evaluated effects of homolog engagement defects restricted to small portions of the genome using karyotypically abnormal yeast strains with a homeologous chromosome V pair, monosomic V, or trisomy XV. We found that homolog engagement-defective chromosomes incurred more DSBs, concomitant with prolonged retention of the DSB-promoting protein Rec114, while the rest of the genome remained unaffected. SC-deficient, crossover-proficient mutants ecm11 and gmc2 experienced increased DSB numbers diagnostic of homolog engagement defects. These findings support the hypothesis that SC formation provokes DSB protein dissociation, leading in turn to loss of a DSB competent state. Our findings show that DSB number is regulated in a chromosome-autonomous fashion and provide insight into how homeostatic DSB controls respond to aneuploidy during meiosis.

A Role for Synaptonemal Complex in Meiotic Mismatch Repair

“…Prior studies indicate that budding yeast SC assembly prevents excess Spo11-initiated DSBs (Subramanian et al . 2016; Mu et al . 2020).…”

“…The budding yeast SC structure thus plays a role in attenuating interhomolog recombination events, possibly by discouraging the accumulation of additional DNA DSBs, and/or by preventing nascent recombination intermediates from engaging with the homolog (versus the sister chromatid) for repair (Subramanian et al . 2016; Mu et al . 2020).…”

Mechanism and Control of Meiotic DNA Double-Strand Break Formation in S. cerevisiae

“…This revealed that excessive DSB formation is controlled by a regulatory feedback mechanism that depends on interhomolog interactions ( Figure 9A , circuit 7). Yeast strains with karyotype abnormalities show accumulation of DSBs specifically on the chromosomes that experience homolog engagement defects, showing that the feedback control operates in a chromosome-autonomous fashion ( Mu et al, 2020 ). Smaller chromosomes also experience higher DSB levels, in part because they take more time to find each other, and as a consequence remain longer in a DSB-competent state due to the persistence of DSB proteins ( Murakami et al, 2020 ).…”

“…Mutations in components of the SC central region (Gmc2 and Ecm11) that abolish SC elongation but not crossover formation show elevated DSBs ( Humphryes and Hochwagen, 2014 ; Voelkel-Meiman et al, 2016 ; Lee et al, 2020 ; Mu et al, 2020 ). This indicates that homolog engagement feedback control operates at the level of SC assembly rather than recombination.…”

“…SC assembly removes Hop1 from the chromosome axis ( Börner et al, 2008 ; Chen et al, 2014 ). This is thought to close the window of opportunity for DSB formation by triggering the dissociation of DSB proteins ( Mu et al, 2020 ; Figure 10C ). Indeed, many DSB proteins (Rec102, Rec104, Rec114, and Mei4) are removed from synapsed chromosomes ( Kee et al, 2004 ; Li et al, 2006 ; Maleki et al, 2007 ; Panizza et al, 2011 ; Carballo et al, 2013 ).…”