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Genetics, Vol. 177, 2525-2530, December 2007, Copyright © 2007
doi:10.1534/genetics.107.080408

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Synthetic Lethal Interactions Identify Phenotypic "Interologs" of the Spindle Assembly Checkpoint Components

Maja Tarailo, Sanja Tarailo and Ann M. Rose1

Department of Medical Genetics, Faculty of Medicine, University of British Columbia, Vancouver, British Columbia V6T 1Z3, Canada

1 Corresponding author: Department of Medical Genetics, Faculty of Medicine, University of British Columbia, NCE, Room 419, 2125 East Mall, Vancouver, BC V6T 1Z4, Canada.
E-mail: ann.rose{at}ubc.ca

Manuscript received August 12, 2007. Accepted for publication September 27, 2007.


   ABSTRACT
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 ABSTRACT
ACKNOWLEDGEMENTS
 LITERATURE CITED
 
Here, we report genetic interactions with mdf-1(gk2)/MAD1 in Caenorhabditis elegans. Nine are evolutionarily conserved or phenotypic "interologs" and two are novel enhancers, hcp-1 and bub-3. We show that HCP-1 and HCP-2, the two CENP-F-related proteins, recently implicated in the spindle assembly checkpoint (SAC) function, do not have identical functions, since hcp-1(RNAi), but not hcp-2(RNAi), enhances the lethality of the SAC mutants.

THE interplay between the kinetochores and the spindle is monitored by a conserved surveillance mechanism, the spindle assembly checkpoint (SAC), which ensures proper chromosome segregation (reviewed in CLEVELAND et al. 2003). In humans, chromosome mis-segregation may cause miscarriage and birth defects or promote neoplasia by amplifying oncogenes or by reducing tumor suppressor gene dosage (reviewed in HASSOLD and HUNT 2001; BHARADWAJ and YU 2004).

In Saccharomyces cerevisiae, proteins responsible for the checkpoint function were identified in screens for genes required to arrest mitosis in the presence of microtubule-depolymerizing drugs. These include five nonessential genes, MAD1, MAD2, MAD3, BUB1, and BUB3, and one essential gene, MPS1 (HOYT et al. 1991; LI and MURRAY 1991; WEISS and WINEY 1996). The SAC components are widely conserved throughout the eukaryotic kingdom (reviewed in CLEVELAND et al. 2003). In humans, mutations in homologs of the checkpoint genes have been reported in a number of different tumors (reviewed in KOPS et al. 2005). In Caenorhabditis elegans, orthologs for five SAC components, mdf-1/MAD1, mdf-2/MAD2, san-1/MAD3, bub-1/BUB1, and Y54G9A.6/BUB3, have been identified (KITAGAWA and ROSE 1999; OEGEMA et al. 2001; NYSTUL et al. 2003; STEIN et al. 2007; TARAILO et al. 2007). Analysis of the mdf-1 deletion mutant, mdf-1(gk2), was the first demonstration that the checkpoint is essential for long-term survival and fertility in a multicellular organism (KITAGAWA and ROSE 1999).

One way to better understand the checkpoint function is to define functional relationships between proteins by creating genetic interaction maps. In yeast, array analysis of deletion strains has been used to identify synthetic lethal interactions between the components of the SAC pathway (LEE and SPENCER 2004; DANIEL et al. 2006). In C. elegans, we successfully used the mdf-1(gk2) mutant to identify downstream components of the metaphase-to-anaphase transition pathway as suppressors of the mdf-1(gk2) lethal phenotype (KITAGAWA et al. 2002; TARAILO et al. 2007). To avoid the difficulties associated with a genetic screen for mutations that enhance mdf-1(gk2) lethality, we used RNA interference (RNAi) by the feeding method (TIMMONS and FIRE 1998) to identify phenotypic "interologs" with mdf-1(gk2)/MAD1. "Interolog" is a term adopted from WALHOUT et al. (2000) who used this term to describe physical interactions that are conserved between species. We focused our initial analysis on the nonessential homologs of the yeast genes that display synthetic lethal interaction with MAD1.

Identification of conserved mdf-1/MAD1 genetic interactions:
We reported previously that mdf-1(gk2) homozygotes segregated from a heterozygous parent have no obvious phenotype in the first generation (KITAGAWA and ROSE 1999; TARAILO et al. 2007). In subsequent generations, genetic errors arise and accumulate, leading to lethality (KITAGAWA and ROSE 1999; TARAILO et al. 2007). We took advantage of the F1 viability to identify nonessential genes that, when disrupted, result in decreased viability of mdf-1(gk2) homozygotes in F1.

We examined whether known MAD1 synthetic lethal interactions observed in yeast were conserved in C. elegans (supplemental Table 1 at http://www.genetics.org/supplemental/). To date, there are 79 MAD1 synthetic lethal interactions identified in S. cerevisiae (WANG and BURKE 1995; HARDWICK et al. 1999; KROGAN et al. 2004; LEE and SPENCER 2004; TONG et al. 2004; MEASDAY et al. 2005; MONTPETIT et al. 2005; BLAKE et al. 2006; DANIEL et al. 2006; PAN et al. 2006). We used reciprocal best BLASTP (ALTSCHUL et al. 1997) analysis to identify putative C. elegans orthologs for 37 of these 79 genes (supplemental Table 1). Of the 42 genes, 14 had matches to more than one C. elegans protein, while 28 did not display significant sequence matches to any of the proteins in the C. elegans genome. Of the 37 putative orthologs, 7 were not present in the C. elegans RNAi library (KAMATH et al. 2003) and 9 were lethal when inactivated by RNAi in both experimental and control strains and therefore could not be assessed for enhancement (supplemental Table 1). Of the 21 nonlethal RNAi targets assayed, 9 were strong enhancers, resulting in a significant alteration of Unc-46 to wild-type ratio in the KR3627 strain, but not in the control KR4144 strain (Figure 1).


Figure 1
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  		FIGURE 1.— Enhancers identify conserved mdf-1/MAD1 genetic interactions. The figure represents a plot of the observed-over-expected ratio of the Unc-46 Mdf-1 worms to wild-type-looking worms for the nine enhancer genes. Individual bacterial RNAi-feeding strains were grown in LB broth with 50 µg/ml ampicillin and 12.5 µg/ml tetracycline at 37° overnight. The bacteria were then streaked on nematode growth media plates containing 50 µg/ml ampicillin, 12.5 µg/ml tetracycline, and 0.5 mM isopropyl-β-D-thiogalactopyranoside. The next day, L4 hermaphrodites of the KR3627 strain [unc-46(e177) mdf-1(gk2) V/nT1 [let-x(m435)] (IV;V)] were plated on these plates and fed dsRNA-expressing bacteria. Their wild-type progeny were plated individually in L4 stage on the corresponding RNAi plates and their progeny were scored. As a control, we used the KR4144 strain [unc-46(e177) V/nT1[let-x(m435)] (IV;V)]. All the RNAi vectors were tested by PCR amplification. In the cases where altered Unc-46 to wild-type-looking worm ratio was observed in the KR3627 strain, but not in the KR4144 strain, the RNAi clone was scored as positive for enhancement. The data obtained are from four independent experiments with >2000 animals assayed. For all experiments, animals were kept at 20°.

 
There are several possible explanations for the inability of 12 synthetic lethal MAD1 interactions to enhance mdf-1(gk2) lethality in C. elegans. First, it is possible that some of the putative orthologs identified by the reciprocal best BLASTP (ALTSCHUL et al. 1997) analysis are not functional orthologs of these genes in C. elegans. Second, the lack of enhancement may be the result of variability in the efficiency of RNAi. Finally, it is likely that the function of the putative orthologs is differentiated in a multicellular organism and that loss of these genes does not result in organismal lethality, but rather has a consequence in a specific tissue. Although all of these explanations are relevant, we favor the latter. MATTHEWS et al. (2001) performed systematic BLAST analysis to identify pairs of putative C. elegans orthologs of known protein–protein interactions in S. cerevisiae to identify conserved physical interactions, or interologs. These authors suggested that the minimal proportion of true interologs that can be detected between these two species (evolutionarily distant by ~900 million years) is between 16 and 31%. In agreement with their analysis of physical interologs, we observed that among the 21 tested genetic interactions, 9 scored positive, which represents a 43% success rate. Thus, it is clear that, similar to protein interaction maps, the genetic interaction maps from one species may be useful in predicting interactions in another species.

Enhancement of the other checkpoint mutants:
To investigate whether the identified interologs display specificity for the mdf-1(gk2)/MAD1 component of the checkpoint or have a more general effect on the SAC pathway, we tested interactions with other SAC components. To date, knockout alleles have been isolated in four components of the SAC: mdf-1, mdf-2, san-1, and bub-1 (KITAGAWA and ROSE 1999; STEIN et al. 2007). We tested the identified enhancers for interactions with mdf-2(tm2910)/MAD2 and san-1(ok1580)/MAD3 knockout alleles; the bub-1(tm2815)/BUB1 deletion allele results in lethality and could not be tested.

To address the effect of a deletion of the mdf-2 checkpoint gene, we have characterized the mdf-2 deletion mutant allele, mdf-2(tm2910). The tm2910 deletion removes 864 nucleotides between intron 3 and exon 6 and is likely to be a null mutation. In contrast to mdf-1(gk2), mdf-2(tm2910) homozygotes can be maintained at 20° indefinitely but display a severely reduced brood size (33 progeny) of which 19% arrest as embryos, 36% arrest as larvae, and 45% develop into adults (Table 1 and Figure 2). The strain also has a high incidence of males (Him) phenotype (3% of the adult progeny are males), which is an indicator of aberrant chromosome segregation. Although the absence of MDF-2 has a profound effect on C. elegans development and a clear effect on genome stability, MDF-2 is not essential for C. elegans survival under normal conditions. Similarly, san-1 is not essential for C. elegans survival as the san-1(ok1580) deletion allele has only a mild phenotype, resulting in ~87% of progeny developing into adults (STEIN et al. 2007; Table 1 and Figure 2).


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  		TABLE 1 Genetic interaction between the mdf-1/MAD1 interologs and the mdf-2/MAD2 and san-1/MAD3 checkpoint components

 

Figure 2
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  		FIGURE 2.— hcp-1(RNAi) and bub-3(RNAi) enhance the mdf-1(gk2) lethality. (A) Observed-over-expected ratio, Unc-46 Mdf-1 worms to wild-type-looking worms, in the KR3627 strain treated with cRNAi (vector with no insert), kbp-5(RNAi), bub-3(RNAi), hcp-1(RNAi), and hcp-2(RNAi). The data obtained are from at least four independent experiments with >2000 animals assayed. (B) The wild-type animals were fed cRNAi, bub-3(RNAi), hcp-1(RNAi), hcp-2(RNAi), and hcp-1/2(RNAi) and the (C) mdf-2(tm2910) and (D) san-1(ok1580) mutants were fed cRNAi, bub-3(RNAi), hcp-1(RNAi), and hcp-2(RNAi). Their progeny were plated individually in L4 stage on the RNAi plates and allowed to lay eggs for 12 hr. The adults were then removed and the embryos were analyzed for the ability to reach adult stage. For each dsRNA, the data obtained represent three independent experiments with >1000 embryos analyzed. Bars represent the mean with SE error bars. The experiments were performed at 20°.

 
Analysis of the nine mdf-1(gk2) enhancers revealed that six significantly enhanced the lethality of mdf-2(tm2910) (Table 1). All six enhancers are conserved genetic interactions with MAD2 and thus represent phenotypic interologs (Figure 3). Furthermore, we observed that three of the six mdf-1(gk2) and mdf-2(tm2910) interactors enhanced the lethality of san-1(ok1580) and are conserved genetic interactions of MAD3 (Table 1 and Figure 3). In addition, none of the 12 genes that failed to enhance the mdf-1(gk2) lethality enhanced the lethality of either mdf-2(tm2910) or san-1(ok1580) (data not shown). Because the SAC components are part of the kinetochore, we asked whether the interactions that we observed are specific to the SAC or if they might act more generally by affecting the kinetochore. As with yeast, we observed that none of the analyzed genes enhanced the lethality of the him-10(e1511ts)/NUF2 kinetochore component mutant (Table 1), suggesting that the identified enhancers have a specific effect on the SAC pathway. The interaction data for mdf-1, mdf-2, and san-1 support previous findings that some synthetic interactions that are common to MAD1 and MAD2 are not shared by MAD3 (LEE and SPENCER 2004; DANIEL et al. 2006; Figure 3), suggesting that, in C. elegans as in yeast, MDF-1/Mad1 and MDF-2/Mad2 have functions that are not shared by SAN-1/Mad3 and that MDF-1 and MDF-2, although closely related, differ in phenotype and in the spectrum of genetic interactions, suggesting overlapping but not identical roles in C. elegans.


Figure 3
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  		FIGURE 3.— Summary of the genetic interaction data. Arrows and circles/squares represent synthetic lethal interactions and C. elegans genes, respectively. Circles represent genes of known function, while squares represent genes of unknown function in C. elegans. The color code for interactions is as follows: red arrows represent detected interologs; black arrows represent synthetic lethal interactions in yeast that were not observed in C. elegans; and blue arrows represent novel interactions identified in worm and not observed in yeast. ORTIZ et al. (1999) suggested homology between Okp1 and CENP-F. EVANS et al. (2007) suggested homology between Okp1 and hcp-1. Okp1 does not display synthetic lethality with any of the SAC components in yeast.

 
Y54G9A.6/BUB3 enhances the lethality of SAC mutants:
Next we tested a putative ortholog of the kinetochore-associated component Bub3, Y54G9A.6 (which we will refer to as bub-3; reviewed in OEGEMA and HYMAN 2006; STEIN et al. 2007; TARAILO et al. 2007), for genetic interaction with SAC mutants. bub-3(RNAi) animals do not display any obvious phenotypes (Figure 2B); however, depletion of BUB-3 in the absence of MDF-1, MDF-2, or SAN-1 results in a significant decrease in viability, presumably due to elevated chromosome instability (Figure 2). We observed that loss of both BUB-3 and SAN-1 caused an increase in chromosome mis-segregation; san-1(ok1580) mutants produced 1% males and the incidence of males was increased twofold in the san-1(ok1580); bub-3(RNAi) animals. In yeast, BUB3 has not been shown to be synthetic lethal with any of the SAC mutants, suggesting a novel interaction (Figure 3). Furthermore, these data provide the first evidence regarding the function of this gene in C. elegans and suggest that BUB-3 functions with the SAC components to ensure proper cell cycle progression.

hcp-1/CENP-F enhances the lethality of SAC mutants:
We investigated kinetochore defects in the absence of the checkpoint. Most kinetochore components are essential in C. elegans (reviewed in OEGEMA and HYMAN 2006); exceptions are kbp-5, hcp-1, and hcp-2. Analysis of these genes revealed that, while the depletion of either KBP-5 or HCP-2 had no obvious effect on mdf-1(gk2) lethality, the depletion of HCP-1 resulted in significant enhancement of the mdf-1(gk2) lethal phenotype (Figure 2A).

In human cells, CENP-F (mitosin), a large 350-kDa transient kinetochore component, associates with the outer kinetochore (RATTNER et al. 1993; LIAO et al. 1995; ZHU et al. 1995). Although the precise function of CENP-F is still unknown, an emerging body of evidence implicates CENP-F in kinetochore maturation, regulation of chromosome behavior, and control of SAC activity (EAKER et al. 2001; HOLT et al. 2005; LAOUKILI et al. 2005; YANG et al. 2005). In C. elegans, HCP-1 and HCP-2, two CENP-F-like proteins, were shown to contribute redundantly to the fidelity of chromosome segregation (MOORE et al. 1999) and to the SAC response in the presence of either chemical or mutational disruptions of the microtubule cytoskeleton (STEAR and ROTH 2004; ENCALADA et al. 2005). CHEESEMAN et al. (2005) proposed that HCP-1 and HCP-2 function redundantly to target the microtubule-associated protein CLASP/CLS-2 to kinetochores, where it may function to promote the polymerization of kinetochore-bound microtubules. We observed that depletion of either HCP-1 or HCP-2 alone did not result in significant developmental arrest in a wild-type background, while codepletion of both proteins resulted in highly penetrant embryonic lethality, chromosome segregation defects, inability to form metaphase plates, and precocious anaphase onset, as previously reported (MOORE et al. 1999; ENCALADA et al. 2005; Figure 2B and data not shown). Furthermore, we observed that depletion of HCP-1 in the absence of MDF-1, MDF-2, or SAN-1 results in a significant decrease in viability (Figure 2). Surprisingly, we observed that depletion of HCP-2 had no obvious effect on viability of the mdf-1(gk2), mdf-2(tm2910), or san-1(ok1580) mutants (Figure 2). We used the mdf-2(vc15) mutant (GILCHRIST et al. 2006) to analyze the fidelity of chromosome segregation in a SAC mutant in the absence of HCP-1. The mdf-2(vc15) homozygote has a milder phenotype than the mdf-2(tm2910) animals, as 89% of progeny develop into adults, of which 0.2% are male, making it easier to identify increased chromosome instability. While depletion of HCP-2 has no effect on mdf-2(vc15) worms, depletion of HCP-1 results in a significant decrease in viability, as only 59% of progeny develop into adults, of which 2% are male. This result suggests that synthetic lethality between hcp-1 and SAC components can be explained by an increase in chromosome instability. Importantly, our results suggest that HCP-1 and HCP-2 may not have completely redundant functions. HCP-1 and HCP-2 share only 54% sequence similarity and HCP-2 lacks the tandem repeats observed in HCP-1 and CENP-F (MOORE et al. 1999). In CENP-F, these tandem repeats are required for strong CENP-F–kinetochore interaction (ZHU 1999). STEAR and ROTH (2004) proposed that the checkpoint pathway, like the chromosome segregation machinery, may not require the functions of both HCP-1/CENP-F and HCP-2. The data presented here support this proposal.

Conclusion:
We have established an assay to identify genes that enhance the lethality of SAC defects. Using this assay, we identified nine genetic interactions with mdf-1/MAD1 conserved between worms and yeast (Figure 3). These phenotypic interologs have a specific effect on the SAC, since six of them enhanced the mdf-2(tm2910)/MAD2 lethality, three also enhanced the san-1(ok1580) lethality (Figure 3), and none enhanced lethality in the kinetochore mutant him-10(e1511ts)/NUF2. These data are the first evidence linking these enhancers to the SAC and genome stability in C. elegans. These conserved interactions show that, similar to protein interaction maps (MATTHEWS et al. 2001), the genetic interaction maps from one species are useful in predicting interactions in another species and in providing insight into the function of uncharacterized proteins. The conservation of pathway function is proposed to extend to human identification of genetic interologs. Identifying targets that take advantage of the weakened SAC to selectively destroy tumor cells without affecting normal cells could lead to more efficient antitumor drugs.

Furthermore, we identified two novel interactions in C. elegans that are not conserved in yeast (Figure 3), suggesting that the function of the putative orthologs may be more specialized in a multicellular organism, resulting in a different consequence upon inactivation. Data presented here underscore the importance of using different model systems to investigate SAC and chromosome instability.


   ACKNOWLEDGEMENTS
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 ABSTRACT
 ACKNOWLEDGEMENTS
LITERATURE CITED
 
We thank the Bioresource Project (Shohei Mitani) for kindly providing the mdf-2(tm2910) mutant. We also thank the C. elegans Gene Knockout Consortium for providing deletion mutants (http://ko.cigenomics.bc.ca/) and the Caenorhabditis Genetics Center for providing the strains. We are especially appreciative of the encouragement provided by Donald Riddle and David Baillie. We also thank Nigel O'Neil, the Rose Lab members, and our reviewers for helpful discussion and comments on the manuscript and Shir Hazir for technical assistance in the study. This work was supported by a University Graduate Fellowship to M.T., a Natural Sciences and Engineering Research Council of Canada (NSERC) scholarship to S.T., and grants from the Canadian Institutes for Health Research and NSERC to A.M.R.


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Communicating editor: K. KEMPHUES




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