The fo ld in g o f th e e u k a ry o tic g e n o m ic D N A in to c h ro m a tin so th a t tr a n s c r ip t io n a l a c tiv it y o f genes d e p e n d s o n c h r o m a tin s tr u c tu r e n e cessitates a m e c h a n is m fo r a re v e rs ib le f o ld in g / r e m o d e llin g o f
ch ro m a tin . In recent years tw o fa m ilie s o f enzym es in v o lv e d in c h ro m a tin re m o d e llin g have been id e n tifie d - S W l/S N F and h istone acetyltransferes. A c c u m u la te d genetic and b io m e d ic a l evidence suggests th a t these tw o fa m ilie s w o rk together (P ollard and Peterson, 1998).
S W I/S N F
A T P - d r i v e n protein complexes. The yeast S W l/S N F is one o f th e best characterised e u k a ry o tic com plexes (RSC (yeast); N U R F , C F IR A C , A C F , B R M (d ro s o p h ila ); B R G l- a n d h B R M - associated (m a m m a ls )). The com plexes c a rry o u t a re la te d b io c h e m ic a l fu n c tio n - the A T P -d riv e n c h ro m a tin assem bly and re m o d e llin g , and co n ta in ATPase u n its as the core co m p on e n ts (K adonaga, 1998). Thus, the ATPase u n it o f the S W l/S N F c o m p le x is S W 12/S N F 2 p ro te in w h ic h b e lo n g s to A T P a s e /h e lic a s e e u k a ry o tic fa m ily w it h o v e r 35 fa m ily m em bers. These ATPases p la y im p o rta n t roles in tra n s c rip tio n and c h ro m a tin a c tiv a tio n (S W 12/S N F2, IS W l, M O T l, b rm , B R G l, hB R M ), D N A re p a ir and re c o m b in a tio n (R A D 5, R A D 1 6 , R A D ), ch ro m o s o m e s e g re g a tio n an d c e ll cycle p ro g re s s io n (S T H /N P S l) and are the core c o m p o n e n ts o f th e p ro te in co m p le xe s m e n tion e d above (C arlson and L a ure n t, 1994).
S W I /S N F protein complex. S W l/S N F is yeast 2 M D a m u lti-s u b u n it p ro te in com p le x capable o f d ire c t a c tiv a tio n o f tra n s c rip tio n b y a lte rin g c h ro m a tin structure. I t has been sh o w n th a t the S W l/S N F com p le x b in d s to D N A and nucleosom es w ith a lo w n a no m o lar a ffin ity and p e rtu rb s the h is to n e -D N A
in te ra c tio n u sin g energy fro m A T P h y d ro ly s is (K w o n et al., 1994; Cote et al., 1994). S W I/S N F fu n c tio n w as d e m o n s tra te d in a series o f e le g a n t e x p e rim e n ts s h o w in g th a t th e S W I/S N F c o m p le x causes 10-30 fo ld s tim u la tio n in the G A L 4 b in d in g to n u cleosom al D N A . U s in g a m o d e l o f nucleosom e arrays it has been fo u n d th a t S W I/S N F actio n does n o t lead to d isp la cem e n t o f octam er b u t ra th e r weakens h is to n e -D N A contacts w it h in nucleosom e in a re ve rsib le m anner. This p e rtu rb e d c o n fo rm a tio n o f the nucleosom e persists fo r some p e rio d a fte r d e ta ch m e n t o f the S W I/S N F c o m p le x, e n h a n cin g a b ility o f the G A L 4 fa c to r to d isp la ce the h is to n e octam er (Cote et al., 1994; O w e n -H u g h es et al., 1996; L o g ie and Peterson, 1997; Cote et al., 1998).
A lth o u g h the S W I/S N F co m p le x is o fte n re fe rre d as a "g lo b a l a c tiv a to r" m a n y p ro te in s o f the com plex tu rn o u t to be no n essential to yeast v ia b ilit y and th e ir m u ta tio n s seems to affect o n ly a re stricte d n u m b e r o f genes. The experim ents o f Peterson and colleagues shed lig h t on w h y some genes m a y need S W I/S N F and some not. In these e xp erim e nts, S W I/S N F w as o n ly re q u ire d fo r the G A L 4 b in d in g w h e n the G A L 4 b in d in g sites w ere w it h in a nucleosom e. W h e n the sites w ere located in the nucleosom e free re g io n s, th e G A L 4 b in d in g an d su b seq u e n t gene a c tiv a tio n d id n o t re q u ire S W I/S N F (Burns and Peterson, 1997). This fin d in g , to g e th e r w it h the fact th a t m a n y yeast genes co n ta in c o n s titu tiv e D N A s e I sites in th e ir u p stre a m re g io n (in d ic a tin g a p o te n tia l nucleosom e-free site) suggests th a t S W I/S N F is necessary o n ly fo r the gene a c tiv a tio n w h e n the a c tiv a to r b in d in g sites are located w it h in nucleosomes.
Ma mm ali an S W I / S N F homologes. M a m m a lia n S W I/S N F co m p le xe s are m ade u p o f 9-12 p ro te in s ra n g in g fro m 47-250 kD a in w e ig h t an d one pre se n t in m u ltip le fo rm s (W a n g et al., 1996). M a m m a ls c o n ta in tw o com plexes h o m o lo g o u s to the S W I2 /S N F 2 gene, BRG and b rm , w h ic h to g e th e r are lik e ly to be essential fo r m am m als a cco rd in g to p re lim in a r y w o rk on ce ll lines (S um i-Ichinose, 1997; C hiba et al., 1994). B o th p u r ifie d B R G l an d h B R M p ro te in s ha ve A T P -d riv e n m o n o -n u c le o s o m e a n d nucleosom e re m o d e llin g a c tiv itie s . Recent stu d ies have s h o w n th a t the B R M - /- m ice e x h ib it an increase in c e ll p r o life ra tio n b u t o th e rw is e are n o rm a l, suggesting th a t BRM can be fu n c tio n a lly replaced b y B R G l p ro te in (Reyes et al., 1998). I t appears therefore, th a t B R G l and hB R M are the m a in m u tu a lly e x c lu s iv e fu n c tio n a l c o m p o n e n ts o f S W I/S N F c o m p le x e s (Phelan et al., 1999). The increased ce ll p ro life ra tio n in the B R M - /- m ice and in some other experim ents on cell lines suggested an im p o rta n t ro le o f the S W I/S N F com p le x in the cell cycle re g u la tio n . These data are in lin e w ith the experim ents d e m o n stra tin g th a t the h B R G l and hB R M are able to b in d the retinoblastom a fa m ily p ro te in s (such as pRB, p l3 0 , p l0 7 ) w h ic h are s h o w n to be in v o lv e d in re g u la tio n o f ce ll cycle (D u n a ie f et al., 1994; Strober et al., 1996). It has been show n th a t D rosophila's B R G l is also able to b in d th e RP p ro te in . M o re o v e r, in a h u m a n c a rc in o m a c e ll lin e the D ro s o p h ila B R G l p ro te in seems to e x h ib it the R B -d e p e n d e n t tu m o u r suppressor a c tiv ity (D un a ief et al., 1994).