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correct chromosome segregation requires that one and only one kinetochore assembles on each chromosome . to achieve this , a subset of kinetochore proteins functions to specifically recognize and bind to centromeric dna . in budding yeast , centromeric
dna is 125 bp long and is conserved among the different chromosomes ( fitzgerald - hayes et al . , 1982 ) .
in contrast , metazoan centromeric dna can be megabases in length and does not contain easily identifiable dna consensus sequences ( for review see choo , 1997 ) . despite the differences between yeast and metazoan centromeric dna , the kinetochores that assemble on this dna in both cases are organized around centromeric nucleosomes that contain specialized histone h3-like proteins ( yeast cse4p or its metazoan homologue cenp - a [ meluh et al . , 1998 ] ) . since cse4p / cenp - a  containing nucleosomes are found only at centromeres , there must be a mechanism to target these nucleosomes specifically to centromeric dna .
yeast have solved this problem in part through the activities of additional dna - binding kinetochore proteins .
the yeast centromeric nucleosome binds to an 80-bp sequence ( termed cdeii ) that spans the middle of the centromere .
the dna sequences on either side of cdeii ( termed cdei and cdeiii ) also serve as binding sites for distinct proteins .
the most important of these is the cbf3 complex ( ndc10p , cep3p , ctf13p , and skp1p ) , which binds to cdeiii ( lechner and carbon , 1991 ) . in the absence of cbf3 ,
kinetochore function is abolished in vivo and in vitro ( goh and kilmartin , 1993 ; sorger et al . , 1994 ) ,
and the association of all known kinetochore proteins with the centromere , including cse4p ( ortiz et al . , 1999 ) , is disrupted .
in contrast , the association of cbf3 with centromere dna in vivo does not require cse4p ( measday et al . , 2002 ) .
therefore , the specific binding of cbf3 to cdeiii helps define the position of the yeast kinetochore .
cdei serves as a binding site for a homodimer of cbf1p ( mellor et al . ,
although cbf1p is not essential for kinetochore function , it induces the bending of dna ( niedenthal et al . , 1993 ) and may therefore contribute to the higher order structure of the kinetochore .
cbf1p has structural similarity and limited sequence identity to cenp - b , which binds to metazoan centromeric dna and also induces dna bending ( tanaka et al . , 2001 ) .
physical and genetic evidence suggests that mif2p , a protein with similarity to metazoan cenp - c , also binds to centromeric dna near cbf1p ( meluh and koshland , 1995 , 1997 ) .
however , despite the presence of dna - binding motifs ( meluh and koshland , 1995 ) mif2p has not been shown to bind directly to this dna sequence in vitro .
based on identified physical interactions , it appears that inner kinetochore proteins do not associate directly with microtubules or the microtubule - binding components of the outer kinetochore .
one important central kinetochore component appears to be the ctf19 complex ( ctf19p , mcm21p , and okp1p ) , which binds to each of the inner kinetochore components described above ( ortiz et al . , 1999 ) . by virtue of its two - hybrid interactions
, the ctf19 complex also appears well positioned to link together the ctf3 complex ( ctf3p , mcm16p , and mcm22p [ measday et al . , 2002 ] ) and the ndc80 complex ( ndc80p , spc24p , spc25p , and nuf2p [ janke et al .
the ndc80 complex is especially important for kinetochore function , since mutants in this complex are completely defective for chromosome segregation , similar to cbf3 mutants .
there are also a variety of kinetochore proteins which are less defined in terms of their physical interactions .
since these proteins have not been shown to bind to either microtubules or centromeric dna , we have tentatively classified them here as central kinetochore proteins .
these include mtw1p , which is essential for kinetochore function with mtw1 - 1 mutants , showing highly abnormal dna segregation ( goshima and yanagida , 2000 ) .
other kinetochore proteins , including slk19p ( zeng et al . , 1999 ) , mcm19p ( ghosh et al . , 2001 ) , chl4p ( roy et al . , 1997 ) , and bir1p ( yoon and carbon , 1999 ) , are not essential for viability and therefore might play redundant or nonessential roles in kinetochore function or structural integrity . although initial studies have indicated that bir1p , a homologue of the metazoan kinetochore passenger protein survivin , shows genetic and two - hybrid interactions with the cbf3 complex ( yoon and carbon , 1999 ) , future work will be required to establish the specific roles that these nonessential proteins play at the kinetochore .
however , until recently it was unclear how yeast kinetochores attach to spindle microtubules . in metazoans , microtubule - associated motors , including cenp - e , dynein , and xkcm1 , play roles in mediating kinetochore 
microtubule attachments and in subsequent chromosome movements during congression and anaphase a ( for review see heald , 2000 ) .
however , yeast kip3p may be an xkcm1 homologue ( severin et al . , 2001 ) , suggesting that it may function at kinetochores .
cin8p , a bimc - related kinesin , associates with kinetochores in vivo ( he et al . , 2001 ) , and in vitro assays have suggested that the motor protein kar3p plays a role in kinetochore function ( middleton and carbon , 1994 ) .
although deletion of cin8 , kar3 , or kip3 individually does not dramatically affect chromosome segregation , cin8 kip3 and kip3 kar3 double mutants are inviable ( miller et al . , 1998 ) , possibly reflecting redundant roles for these motors at the kinetochore .
nonmotor microtubule - associated proteins ( maps ) * also appear to play roles in mediating kinetochore 
the first kinetochore - associated map to be identified was dam1p , a component of the dam1p complex ( dam1p , duo1p , dad1p , spc19p , spc34p , dad2p , ask1p , dad3p , and dad4p [ cheeseman et al .
this complex localizes to kinetochores in an ndc10- and ndc80-dependent manner ( enquist - newman et al . , 2001 ; jones et al . , 2001
phenotypic analyses of dam1 mutants showed that their spindles have monopolar attachments to paired sister chromatids ( cheeseman et al .
, 2001b ; he et al . , 2001 ) , possibly reflecting an inability to form new kinetochore 
microtubule attachments or a role in chromosome biorientation ( janke et al . , 2002 ) .
the dam1p complex interacts physically with central kinetochore proteins of both the ctf3 and ndc80 complexes ( fig .
2 ) ( cheeseman et al . , 2001a ; measday et al . , 2002 ) .
this model is based on the organization of the dna - binding proteins ( espelin et al .
, 1997 ; meluh and koshland , 1997 ; meluh et al . , 1998 ) and the known physical interactions of the different kinetochore proteins ( cheeseman et al . , 2001a ) .
electron microscope studies of vertebrate kinetochores revealed that microtubule plus ends make end - on attachments with the kinetochore .
although there is no direct evidence for such an end - on attachment in yeast , bik1p , a member of the clip-170 family of plus - end tracking maps , does localize to kinetochores independent of its microtubule - binding activity ( he et al .
however , in polyploid cells , highly sensitive to disrupted kinetochore function because of numerous spindle connections , these bik1 mutants show defects in chromosome segregation ( lin et al . , 2001 ) .
 binding map of the eb1 family , may also play a role in kinetochore function .
in fact , bim1 mutants show genetic interactions with genes encoding a variety of kinetochore components ( tong et al . , 2001 ) .
additional studies have also implicated stu2p , a homologue of the microtubule stabilizing protein xmap215 , in kinetochore function ( he et al . , 2001 ) . a similar role was suggested independently for the schizosaccharomyces pombe stu2p homologues , dis1 and mtc1 ( nakaseko et al . , 2001 ) .
however , as with other maps that play multiple roles in spindle function the significance of these results is unclear .
although stu2 mutants show altered chromosome dynamics ( he et al . , 2001 ) , stu2p plays a key role in modulating microtubule dynamics ( severin et al . , 2001 ) .
therefore , altered chromosome dynamics may reflect microtubule defects instead of a role for stu2p in mediating kinetochore  microtubule interactions .
to ensure that the kinetochore proteins described above function properly , the conserved mitotic checkpoint ( fig .
microtubule attachments and , in the event of an error , arrests a cell in metaphase ( for review see amon , 1999 ) . in budding yeast , the primary signal for this checkpoint is the absence of an attachment between the centromere and the spindle , implicating kinetochore proteins as the source of this signal . in fact , mutants in several kinetochore proteins , including ndc10p , ctf13p , cep3p , spc24p , and spc25p , are defective for the mitotic checkpoint ( gardner et al . , 2001
; janke et al . , 2001 ) , indicating either that an intact kinetochore is required for checkpoint function or that these proteins signal to the mitotic checkpoint .
in addition to sensing attachment defects , the yeast mitotic checkpoint also appears to monitor tension on the kinetochore .
bipolar attachments exert sufficient force on the kinetochore to pull centromeric regions apart before anaphase ( goshima and yanagida , 2000 ; he et al . , 2000 ) .
interestingly , a lack of tension can temporarily activate the yeast mitotic checkpoint even when kinetochore 
. although the classically defined checkpoint components are necessary for this tension checkpoint , it additionally requires ipl1p ( biggins and murray , 2001 ) , an aurora protein kinase .
centromeres are positioned near the spindle poles throughout the cell cycle ( jin et al . , 2000 )
. this localization requires microtubules and functional kinetochores , suggesting that active attachments between the spindle and the kinetochore exist during the majority of the cell cycle .
however , changes in kinetochore function may occur during events such as the assembly of a new kinetochore , during spindle assembly to facilitate the formation of bipolar attachments , and during anaphase a when kinetochores move to the spindle poles .
several proteins have been identified that may regulate these and other aspects of kinetochore function .
the best characterized of these regulatory factors is the ipl1p protein kinase , which is essential for chromosome segregation .
ipl1p can associate with kinetochores ( biggins and murray , 2001 ; kang et al . , 2001 ) and directly with microtubules ( kang et al . , 2001 ) .
ipl1p associates closely in vivo with sli15p , an incenp homologue that plays a role in activating ipl1p 's kinase activity and possibly in substrate recognition ( kang et al .
both ipl1 and sli15 mutants show high frequencies of chromosome missegregation and monopolar attachments of paired sister chromatids to the spindle ( biggins et al . , 1999 ;
microtubule attachments in vitro by phosphorylating the cbf3 subunit ndc10p ( biggins et al . , 1999 ) .
in addition , ipl1p phosphorylates dam1p in vivo and in vitro ( kang et al . , 2001 ) , consistent with the indistinguishable chromosome missegregation phenotypes observed for mutants of each protein .
recently , it was shown that kinetochores are unable to detach from the spindle pole in ipl1 mutants , suggesting that a primary function for ipl1p is promoting the turnover of these attachments to facilitate sister chromatid biorientation ( tanaka et al . , 2002 ) .
the work described here has led to the most detailed molecular picture of an intact kinetochore in any organism .
1 and 2 are an attempt to synthesize what is currently known about the protein composition of the budding yeast kinetochore and how these proteins associate with each other , centromeric dna , and the spindle .
although it is possible that some yeast kinetochore proteins remain unidentified , the diagram shown in fig . 2 provides a useful working model for understanding kinetochore function and should allow predictions to be made on the order of assembly of proteins at the kinetochore .
future work must address issues such as the specific functions of individual kinetochore proteins , how kinetochores move to the poles in anaphase a , how kinetochore assembly and function are regulated , and how unattached kinetochores activate the mitotic checkpoint . with a large list of kinetochore proteins in hand and with knowledge of the specific interactions and biological importance of many kinetochore components , the answers to these questions should now be accessible .
although the budding yeast centromere is extremely short ( 125 bp ) compared to those of other eukaryotes , the kinetochore that assembles on this dna displays a rich molecular complexity . here , we describe recent advances in our understanding of kinetochore function in budding yeast and present a model describing the attachment that is formed between spindle microtubules and centromeric dna . 
 this analysis may provide general principles for kinetochore function and regulation .