Competing Crossover Pathways Act During Meiosis in Saccharomyces cerevisiae

Abstract

In Saccharomyces cerevisiae the MSH4-MSH5, MLH1-MLH3, and MUS81-MMS4 complexes act to promote crossing over during meiosis. MSH4-MSH5, but not MUS81-MMS4, promotes crossovers that display interference. A role for MLH1-MLH3 in crossover control is less clear partly because mlh1⌬ mutants retain crossover interference yet display a decrease in crossing over that is only slightly less severe than that seen in msh4⌬ and msh5⌬ mutants. We analyzed the effects of msh5⌬, mlh1⌬, and mms4⌬ single, double, and triple mutants on meiotic crossing over at four consecutive genetic intervals on chromosome XV using newly developed computer software. mlh1⌬ mms4⌬ double mutants displayed the largest decrease in crossing over (13-to 15-fold) of all mutant combinations, yet these strains displayed relatively high spore viability (42%). In contrast, msh5⌬ mms4⌬ and msh5⌬ mms4⌬ mlh1⌬ mutants displayed smaller decreases in crossing over (4-to 6-fold); however, spore viability (18-19%) was lower in these strains than in mlh1⌬ mms4⌬ strains. These data suggest that meiotic crossing over can occur in yeast through three distinct crossover pathways. In one pathway, MUS81-MMS4 promotes interference-independent crossing over; in a second pathway, both MSH4-MSH5 and MLH1-MLH3 promote interference-dependent crossovers. A third pathway, which appears to be repressed by MSH4-MSH5, yields deleterious crossovers. I N most eukaryotic organisms the correct segregation in both reciprocal exchanges, termed crossovers (CO), and of chromosomes at the first meiotic division requires nonreciprocal exchanges, termed noncrossovers (NCO). reciprocal exchange between homologs. The physicalThe classical double-strand break repair (DSBR) model manifestations of these crossover events, chiasmata, proproposes that these events result from alternative resoluvide the contacts between homologous chromosomes tions of a common Holliday junction intermediate (rethat are necessary for segregation ( Jones 1987). This viewed in Pâques and Haber 1999). Recent studies, cohesion or "chiasma binder" function ensures the genhowever, have suggested that COs and NCOs are proeration of a bipolar spindle in which tension is genercessed via separate pathways. In support of this idea, ated at the kinetochores (Maguire 1974

Multiple branches of the meiotic recombination pathway contribute independently to homolog pairing and stable juxtaposition during meiosis in budding yeast

“…In support of this, ∼17% of the wild-type crossover level is still detected in an mms4⌬ msh5⌬ double mutant (de los Santos et al 2003). A recent study also presents evidence for a branch of the DSB repair pathway separate from those branches dependent on MMS4 and MSH5 function (Argueso et al 2004).…”

“…Since Mus81 and Mms4 are known to promote the CR II pathway that was recently shown to be distinct from the CR I pathway (de los Santos et al 2003;Argueso et al 2004;Borner et al 2004), we tested the involvement of Mus81 in CSHJ. Allelic and ectopic interactions in wild-type, mus81⌬, mus81⌬ ndj1⌬, mus81⌬ mer3⌬, mer3⌬ ndj1⌬, and mus81⌬ mer3⌬ ndj1⌬ strains assayed in parallel indicated no negative effect of the mus81⌬ mutation on either allelic or ectopic interactions ( Fig.…”

Local chromosome context is a major determinant of crossover pathway biochemistry during budding yeast meiosis

“…Most of the remaining events are repaired by a meiosis-specific CO pathway, in which an ensemble of meiotic proteins, called the ZMM proteins, stabilize early recombination intermediates and promote their maturation into double Holliday junction joint molecules (Allers and Lichten, 2001a;Bö rner et al, 2004;Lynn et al, 2007;Schwacha and Kleckner, 1994). These ZMM-stabilized joint molecules (JMs) are subsequently resolved as COs (Sourirajan and Lichten, 2008) through the action of the MutLg complex, which contains the Mlh1, Mlh3, and Exo1 proteins (Argueso et al, 2004;Khazanehdari and Borts, 2000;Wang et al, 1999;Zakharyevich et al, 2010Zakharyevich et al, , 2012. MutLg does not appear to make significant contributions to mitotic COs (Ira et al, 2003).…”

“…MutLg does not appear to make significant contributions to mitotic COs (Ira et al, 2003). A minority of events form ZMM-independent JMs that are resolved as both COs and NCOs by the structure-selective nucleases (SSNs) Mus81-Mms4, Yen1, and Slx1-Slx4, which are responsible for most JM resolution during mitosis (Argueso et al, 2004;Santos et al, 2003;De Muyt et al, 2012;Ho et al, 2010;Muñoz-Galván et al, 2012;Zakharyevich et al, 2012; reviewed by Wyatt and West, 2014). A similar picture, with MutLg forming most meiotic COs and SSNs playing a minor role, is observed in several other eukaryotes (Berchowitz et al, 2007;Holloway et al, 2008;Plug et al, 1998).…”

Regulating double-stranded DNA break repair towards crossover or non-crossover during mammalian meiosis

“…Strains carrying mutations in one of these genes have a reduction of CO whereas NCO are, in general, not affected. In addition, formation of CO in this pathway also requires Mlh1 and Mlh3 proteins, thought to act at a late step in the recombination reaction (Hunter & Borts 1997, Wang et al 1999, Alpi et al 2003, Argueso et al 2004. A unique manifestation of CO regulation is positive interference which leads to the non-random distribution of CO that are more widely spaced than expected (Jones 1984).…”