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The Budding Yeast Msh4 Protein Functions in Chromosome Synapsis and the Regulation of Crossover Distribution

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The Budding Yeast Msh4 Protein Functions in Chromosome Synapsis and the Regulation of Crossover Distribution Copyright 2001 by the Genetics Society of America The Budding Yeast Msh4 Protein Functions in Chromosome Synapsis and the Regulation of Crossover Distribution Janet E. Novak,* Petra B. Ross-Macdonald*,1 and G. Shirleen Roeder*,†,‡ *Department of Molecular, Cellular and Developmental Biology, †Howard Hughes Medical Institute and ‡Department of Genetics, Yale University, New Haven, Connecticut 06520-8103 Manuscript received February 9, 2001 Accepted for publication April 24, 2001 ABSTRACT The budding yeast MSH4 gene encodes a MutS homolog produced specifically in meiotic cells. Msh4 is not required for meiotic mismatch repair or gene conversion, but it is required for wild-type levels of crossing over. Here, we show that a msh4 null mutation substantially decreases crossover interference. With respect to the defect in interference and the level of crossing over, msh4 is similar to the zip1 mutant, which lacks a structural component of the synaptonemal complex (SC). Furthermore, epistasis tests indicate that msh4 and zip1 affect the same subset of meiotic crossovers. In the msh4 mutant, SC formation is delayed compared to wild type, and full synapsis is achieved in only about half of all nuclei. The simultaneous defects in synapsis and interference observed in msh4 (and also zip1 and ndj1/tam1) suggest a role for the SC in mediating interference. The Msh4 protein localizes to discrete foci on meiotic chromosomes and colocalizes with Zip2, a protein involved in the initiation of chromosome synapsis. Both Zip2 and Zip1 are required for the normal localization of Msh4 to chromosomes, raising the possibility that the zip1 and zip2 defects in crossing over are indirect, resulting from the failure to localize Msh4 properly. EDUCTIONAL chromosome segregation is unique match correction; instead, they are required specifically R to the first division of meiosis. Sister chromatids for wild-type levels of meiotic crossing over. In the ab- remain associated throughout this division, while ho- sence of Msh4 or Msh5, meiotic gene conversion occurs mologous chromosomes segregate to opposite poles of at approximately wild-type levels, but crossing over is the spindle apparatus. The chromosome content of a reduced two- to threefold. The MSH4 and MSH5 genes diploid cell is thereby reduced to the haploid number are expressed specifically in meiotic cells (Ross-Mac- of chromosomes. A prerequisite to proper chromosome donald and Roeder 1994; Chu et al. 1998). The pro- segregation at meiosis I is meiotic recombination. Cross- teins directly interact to form a complex (Pochart et ing over establishes chromatin bridges between homo- al. 1997), and they colocalize to foci on meiotic chromo- logs, called chiasmata, that ensure the proper orienta- somes (J. E. Novak, unpublished data). In the absence tion of chromosomes on the meiosis I spindle (Roeder of Msh4 (and presumably also Msh5), chromosomes 1997). The proper segregation of chromosomes in mei- sometimes fail to undergo crossing over (Ross-Mac- osis also depends on formation of the synaptonemal donald and Roeder 1994). Because nonrecombinant complex (SC), an elaborate proteinaceous structure chromosomes often missegregate at meiosis I, the msh4 that holds homologous chromosomes close together and msh5 mutants display reduced spore viability. along their lengths during the pachytene stage of mei- The recombination phenotype of msh4 and msh5 is otic prophase (Roeder 1997). Mutations in genes not unique to these mutants. Mutations in a number of encoding structural components of the SC lead to ho- other yeast genes also reduce the frequency of meiotic molog nondisjunction at meiosis I and precocious sepa- crossing over without decreasing the frequency of non- ration of sister chromatids (Roeder 1997). Mendelian segregation. These genes include ZIP1, ZIP2, Two budding yeast proteins involved in meiotic re- ZIP3, MER3, MLH1, MLH3, and EXO1. The three ZIP combination are Msh4 and Msh5 (Ross-Macdonald genes are involved in SC formation. The Zip1 protein and Roeder 1994; Hollingsworth et al. 1995), which is present along the lengths of synapsed meiotic chromo- are homologs of the bacterial MutS mismatch repair somes and serves as a major structural component of protein. However, Msh4 and Msh5 play no role in mis- the SC (Sym et al. 1993; Sym and Roeder 1995; Tung and Roeder 1998; Dong and Roeder 2000). Zip2 and Zip3 are present on meiotic chromosomes at discrete Corresponding author: G. Shirleen Roeder, Howard Hughes Medical foci that correspond to the sites where synapsis initiates, Institute, Department of Molecular, Cellular and Developmental Biol- and these proteins are required for the normal polymer- ogy, Yale University, P.O. Box 208103, New Haven, CT 06520-8103. E-mail: [email protected] ization of Zip1 along chromosomes (Chua and Roeder 1 Current address: Bristol-Myers Squibb, Applied Genomics, P.O. Box 1998; Agarwal and Roeder 2000). The MER3 gene is 5400, Princeton, NJ 08543-5400. expressed specifically in meiotic cells and encodes a Genetics 158: 1013–1025 ( July 2001) 1014 J. E. Novak, P. B. Ross-Macdonald and G. S. Roeder putative helicase (Nakagawa and Ogawa 1999). The significantly reduces crossover interference and results two MutL homologs, Mlh1 and Mlh3, form a hetero- in SC formation that is delayed and often incomplete. dimer specifically involved in meiotic crossing over Msh4 colocalizes with the Zip2 protein at sites of synapsis (Hunter and Borts 1997; Wang et al. 1999); Mlh1 also initiation and depends on both Zip2 and Zip1 for functions in mismatch repair both in vegetative and proper localization to chromosomes. Analysis of a msh4 meiotic cells (Kolodner and Marsischky 1999). The zip1 double mutant indicates that Msh4 and Zip1 act in Exo1 protein is a 5Ј to 3Ј exonuclease specific for dou- the same pathway of crossing over. ble-stranded DNA (Huang and Symington 1993; Fio- rentini et al. 1997). In addition to its role in meiotic MATERIALS AND METHODS crossing over (Khazanehdari and Borts 2000; Kirk- patrick et al. 2000; Tsubouchi and Ogawa 2000), Exo1 Plasmids, disruptions, and strains: Media were prepared is involved in mismatch repair and recombination in and yeast manipulations were carried out using standard pro- vegetative cells (Fiorentini et al. 1997; Tishkoff et al. cedures (Sherman et al. 1986). All yeast transformants were verified by Southern blot analysis. Yeast strain genotypes are 1997). given in Table 1. Meiotic crossovers are nonrandomly distributed along MSH4 gene disruptions were engineered as follows. chromosomes such that two crossovers rarely occur close pmsh4⌬85-2395 was derived from p6K (Ross-Macdonald and together—a phenomenon known as crossover interfer- Roeder 1994) by inserting linkers containing a NotI site into ence. Interference is generally assumed to involve the a BstBI site at nucleotide 80 and an SspI site at nucleotide 2393 within the MSH4 coding region. Appropriate NotI-BamHI transmission of an inhibitory signal from one crossover and NotI-EcoRI fragments were ligated into pUC18 cut with site to nearby potential sites of crossing over. In budding EcoRI and BamHI to yield pmsh4⌬85-2395, in which nucleo- yeast, mutations in three different genes—ZIP1, NDJ1 tides 85–2395 were replaced with GCGGCCGCAA. To create ⌬ ⌬ (a.k.a. TAM1), and MER3—have been shown to reduce pmsh4 ADE, pmsh4 85-2395 was digested with NotI; the ends were filled in with the Klenow fragment of DNA polymerase or abolish crossover interference (Sym and Roeder I and a 3.7-kb blunt-ended fragment containing the ADE2 1994; Chua and Roeder 1997; Nakagawa and Ogawa gene was inserted. The msh4::ADE2 mutation was introduced 1999). A zip1 null mutation abolishes SC formation into yeast by substitutive transformation (Rothstein 1991) (Sym et al. 1993), while an ndj1 null mutation causes a using pmsh4⌬ADE digested with NcoI and BamHI. p6H, con- substantial delay in SC formation (Chua and Roeder taining msh4::LEU2, was derived from p5E (Ross-Macdonald and Roeder 1994) by cutting with NdeI and circularizing the 1997; Conrad et al. 1997). mer3 has not been tested for fragment containing MSH4 sequences, resulting in a plasmid its effect on synapsis. The observed correlation between in which part of a transposon (including LEU2) replaces nucle- impaired synapsis and decreased interference in mu- otides 168–2290 of the MSH4 coding region. The msh4::LEU2 tants of yeast and other organisms (Moens 1969; Hav- disruption was introduced into yeast by transformation with ekes et al. 1994) is consistent with the hypothesis that p6H cut with NotI. Strains producing tagged versions of the Msh4 protein were the SC is involved in transmission of the inhibitory signal constructed as follows. In pU-Msh4-HA, a SacI-XhoI fragment responsible for interference (Egel 1978; Maguire 1988). containing the MSH4 gene marked with three copies of the The observation that Schizosaccharomyces pombe and Asper- HA tag at the 3Ј end was obtained from pJ8 (Ross-Macdonald gillus nidulans lack both SC and interference further and Roeder 1994) and inserted between the XhoI and the SacI sites of pRS306 (Sikorski and Hieter 1989). The MSH4- supports this idea (Strickland 1958; Olson and Zim- HA gene was integrated (Rothstein 1991) at URA3 by trans- mermann 1978; Egel-Mitani et al. 1982; Bahler et al. formation with pU-Msh4-HA targeted with StuI. pkan-Msh4C- 1993). 3ϫHA was designed to allow simultaneous disruption of MSH4 Meiotic crossovers are nonrandomly distributed not and insertion of MSH4-HA. To make pkan-Msh4C-3ϫHA, p10H only along chromosomes, but also among chromo- (Ross-Macdonald and Roeder 1994) was cut with BstUI and EcoRI, and the 2.4-kb fragment containing the downstream somes. In most meioses, every chromosome pair, no portion of MSH4-HA was inserted into pFA6-Kan-MX4 (Wach matter how small, sustains at least one crossover—a et al. 1994) cut with EcoRI and EcoRV. The msh4::MSH4-HA- so-called obligate crossover or obligate chiasma.
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