Abstract
Crossovers (COs) play a critical role in ensuring proper alignment and segregation of homologous chromosomes during meiosis. How the cell balances recombination between CO vs. noncrossover (NCO) outcomes is not completely understood. Further lacking is what constrains the extent of DNA repair such that multiple events do not arise from a single double-strand break (DSB). Here, by interpreting signatures that result from recombination genome-wide, we find that synaptonemal complex proteins promote crossing over in distinct ways. Our results suggest that Zip3 (RNF212) promotes biased cutting of the double Holliday-junction (dHJ) intermediate whereas surprisingly Msh4 does not. Moreover, detailed examination of conversion tracts in sgs1 and mms4-md mutants reveal distinct aberrant recombination events involving multiple chromatid invasions. In sgs1 mutants, these multiple invasions are generally multichromatid involving 3–4 chromatids; in mms4-md mutants the multiple invasions preferentially resolve into one or two chromatids. Our analysis suggests that Mus81/Mms4 (Eme1), rather than just being a minor resolvase for COs is crucial for both COs and NCOs in preventing chromosome entanglements by removing 3′- flaps to promote second-end capture. Together our results force a reevaluation of how key recombination enzymes collaborate to specify the outcome of meiotic DNA repair.
Highlights
Homologous recombination during meiosis plays an integral role in ensuring that each gamete receives exactly one copy of each chromosome from its diploid parent
A minority of NCOs may arise through unbiased cutting of the joint molecules (JM) [6] (Figure 1), the bulk of NCOs appears to form via synthesis-dependent strand annealing (SDSA) [7,8,9] or by topoisomerase-assisted dissolution [8]
We find that one protein, Zip3, can direct biased cleavage of the double Holliday-junction (dHJ) intermediate but another protein, Msh4, in the same complex cannot
Summary
Homologous recombination during meiosis plays an integral role in ensuring that each gamete receives exactly one copy of each chromosome from its diploid parent. Given the adverse consequences stemming from problems in crossing over, there is a clear need to understand the underlying mechanisms by which COs are controlled, how the cell balances the choice of partner for recombination: intersister (IS) vs interhomolog (IH) and the choice in pathway: reciprocal exchange resulting in COs vs nonreciprocal exchange resulting in NCOs. Based on budding yeast studies [2,3,4], COs are thought to mainly arise from biased resolution of dHJ intermediates that can be observed physically as joint molecules (JM) using 2D gels [5]. The difference in the formation of COs and NCOs is further highlighted by the fact that NCO formation is independent of Cdc, a polo-like kinase, whereas COs require Cdc activity for JM resolution [11] Taken together these studies clearly point to distinct mechanisms and intermediates that exist in the formation of COs vs NCOs during meiosis
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