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Adherin: Key to the Cohesin Ring and Cornelia de Lange Syndrome
Current Biology, Vol. 14, R834–R836, October 5, 2004, ©2004 Elsevier Ltd. All rights reserved. DOI 10.1016/j.cub.2004.09.035
Dispatch
Adherin: Key to the Cohesin Ring and Cornelia de Lange Syndrome Dale Dorsett
Adherin facilitates sister chromatid cohesion, DNA repair and binding of the cohesin complex to chromosomes. New studies indicate that adherin activity is coordinated with DNA replication and chromosome segregation, and that its dosage is critical for gene expression and human development.
A recent flurry of papers provides new insights into how the adherin proteins (Table 1) regulate diverse chromosomal functions and development. Adherin functions were originally revealed by genetic mutations in fungi: the rad9-1 adherin mutant of the mushroom Coprinus cinereus is defective in meiotic DNA repair, chromatid cohesin and homolog pairing [1]; mis4 adherin mutants of the fission yeast Schizosaccharomyces pombe display DNA repair and mitotic sister chromatid cohesion defects [2]; and scc2 adherin mutations in the budding yeast Saccharomyces cerevisiae disrupt mitotic chromatid cohesion [3]. A number of new papers report evidence that the chromosome cohesion function of adherin is conserved in higher organisms. Rollins et al. [4] found Drosophila Nipped-B adherin mutations, which reduce transcriptional activation of homeotic genes by distant enhancer sequences [5], also cause cohesion defects. Gillespie and Hirano [6] have shown that depletion of both isoforms of the Xenopus adherin XScc2 from egg extracts blocks cohesion. And in a dramatic development, Krantz et al. [7] and Tonkin et al. [8] report that human NIPBL adherin mutations cause Cornelia de Lange syndrome, which affects many aspects of physical and mental growth. The adherins of different organisms are homologous and contain several HEAT repeats, protein interaction motifs which are conserved in spacing and position [9]. A key question is whether the diverse roles of adherins in cohesion, DNA repair, gene expression and development reflect a single function, or multiple different mechanisms. The known adherin function is to facilitate chromosomal binding of the cohesin protein complex that holds sister chromatids together [10,11]. Cohesin is one of many ‘structural maintenance of chromosome’ (SMC) complexes, conserved in overall structure from bacteria to man, which play diverse roles in chromosome architecture and function (reviewed in [12]). Cohesin consists of Smc1, Smc3, Rad21 (Mcd1/Scc1) and Scc3 (Stromalin) subunits (Figure 1). Smc1 and Smc3 interact to form a V-like structure with two ATPase head domains, and Rad21 interacts with both ATPase domains to form a ring-like Edward A. Doisy Department of Biochemistry and Molecular Biology, Saint Louis University School of Medicine, Saint Louis, Missouri 63104, USA.
structure. In budding yeast, cohesin binds every 10 kilobases or so along the chromosomes, preferring regions between convergent transcription units [13,14]. An attractive model for cohesion is that the cohesin ring encircles DNA so that subsequent replication captures the two sister chromatids within the ring [15] (Figure 1). Other possibilities include a ‘snap’ model in which two cohesin rings bound to the two sister chromatids loop through each other [16]. In either case, establishing cohesion requires opening of the cohesin ring. ATP hydrolysis mutations in the cohesin ATPase domains and scc2 adherin mutations have the same effect: cohesin rings form but fail to bind to chromosomes [17,18]. This raises the idea that adherins stimulate ATP hydrolysis and ring opening [17] (Figure 1). Small amounts of cohesin subunits co-purify with the Scc2/Scc4 adherin complex, indicating that adherin acts directly on cohesin [17]. Recent chromatin immunoprecipitation experiments with scc2 mutants by Lengronne et al. [14] support this idea, because they indicate that cohesin loads at adherin binding sites and translocates away (Figure 1). Recent experiments with Xenopus egg extracts by Gillespie and Hirano [6] and Takahashi et al. [19] indicate that binding of adherins to chromosomes is regulated to coordinate sister chromatid cohesion and DNA replication (Figure 1). Both groups found that geminin inhibition of Cdt1, an essential component of the pre-replication complex that binds origins of DNA replication, reduced chromosomal association of the XScc2 adherin and cohesin. Moreover, depletion of the XOrc1 component of the origin recognition complex [6,19] or the Mcm2–7 complex that licenses origins [19], also blocked adherin binding. In contrast, blocking initiation of DNA replication or origin unwinding with p21CIP1 [6] or p27Kip [19] had no detectable effect on binding of adherin and cohesin to chromatin. Dissociation of adherin from chromatin in prophase was blocked by depletion of the cdc2 mitotic kinase, while depletion of polo-like and aurora B kinases, required for prophase dissociation of cohesin, had no effect on adherin binding [6]. It remains to be seen if the protein complexes that bind to replication origins Table 1. Adherins and their functions. Organism
Adherin
Demonstrated functions
C. cinereus
Rad9
Meiotic DNA repair, chromatid cohesion, homolog pairing
S. pombe
Mis4
Mitotic sister chromatid cohesion, DNA repair
S. cerevisiae
Scc2
Mitotic sister chromatid cohesion
Drosophila
Nipped-B Long-range gene activation, sister chromatid cohesion
Xenopus
XScc2A,B Mitotic sister chromatid cohesion
H. sapiens
NIPBL-A,B Physical and mental development
Current Biology R835
Figure 1. Proposed mechanisms for binding of adherin and cohesin to chromosomes. Recent work indicates that licensing of DNA replication origins, which involves binding of the origin recognition complex (ORC), Cdt1, and the Mcm2–7 complex, stimulates chromosomal binding of adherin by an unknown mechanism [6,19]. Adherin is proposed to stimulate ATP hydrolysis and opening of the cohesin ring to facilitate entry of the chromosome into the cohesin ring [17]. Subsequent DNA replication would trap both sister chromatids in the cohesin ring. From the opposing effects of adherin and cohesin on gene expression, it is proposed that adherin also facilitates localized or temporary removal of cohesin to allow long-range gene activation [4]. Prophase removal of adherin from chromosomes is stimulated by cdc2 mitotic kinase, but not by polo-like kinase or aurora B kinase, which are required for prophase cohesin removal [6].
Mcm2-7
Replication origin licensing adherin binding
Adherin ORC
Cdt1
Cohesin Rad21/Mcd1/Scc1
Stromalin/Scc3 ADP+Pi
Smc1+Smc3 ATP
Cohesin loading
DNA replication
ADP+Pi
Localized cohesin removal gene activation
Prophase adherin and cohesin removal
Polo-like kinase aurora B
ATP
Cdc2
Current Biology
directly recruit adherin, or if formation of originbinding complexes initiates a signal that alters the ability of adherin to bind to chromatin. In addition to sister chromatid cohesion, chromosomal loading of cohesin by adherins can also explain their role in DNA repair. Human cohesin is recruited to sites of DNA damage, and this recruitment depends on Mre11, a critical component of a complex that binds chromosome breaks and is required for recombination and repair [20]. The mushroom adherin Rad9 functions in an Mre11-dependent repair pathway [1]. So beyond fulfilling a basic requirement for chromatid juxtaposition for repair, it seems likely that adherins load additional cohesin at DNA damage sites. The recent experiments by Rollins et al. [4] raise the possibility that adherin may remove cohesin from chromosomes to facilitate gene expression. The Drosophila adherin Nipped-B facilitates long-range activation of the cut and Ultrabithorax homeotic genes by distant transcriptional enhancers in a dosagesensitive manner [5]. Partial reduction of Nipped-B function reduces activation of these genes, while
complete loss of Nipped-B function causes cohesion defects [4,5]. Surprisingly, Nipped-B and cohesin have opposing effects on gene expression, and partial reduction of cohesin subunits increased cut activation without causing cohesion defects [4]. This dichotomy can be explained if cohesin blocks enhancer–promoter interactions, and Nipped-B facilitates activation by removing cohesin. If adherin opens the cohesin ring, this could aid both cohesin loading and removal of cohesin from chromosomes (Figure 1). There may be a steady state between chromosomal and extra-chromosomal cohesin, with the adherin level determining the on–off rates and opportunities for gene activation. It is also possible, however, that cohesin inhibits gene expression by preventing adherin from performing another task that supports activation. Dissecting the roles of adherin and cohesin in gene activation will be critical for understanding Cornelia de Lange syndrome, which displays a variety of developmental deficiencies, including growth, upper limb, cardiac, gastroesophageal and learning defects.
Dispatch R836
Krantz et al. [7] and Tonkin et al. [8] showed that this syndrome, which occurs as frequently as once per 10,000 births, is caused by spontaneous loss-offunction mutations in one copy of the human NIPBL adherin gene. Because the developmental symptoms are caused by reduced adherin dosage, they likely reflect gene expression changes as opposed to cohesion or repair defects. Indeed, effects on homeotic gene expression similar to those caused by partial loss of Drosophila adherin might explain many features of Cornelia de Lange syndrome, such as upper limb abnormalities. The Xenopus egg studies by Gillespie and Hirano [6] and Takahashi et al. [19] show that the binding and removal of adherin to and from chromosomes are coordinated with replication origin licensing and mitotic entry, which ensures that cohesion and loss of cohesion are properly synchronized with DNA replication and chromosome segregation. This also means, however, that cohesin is bound to chromosomes throughout interphase. Given the sensitivity of homeotic gene expression to small changes in adherin and cohesin dosage, and the devastating developmental consequences of such changes as evidenced by Cornelia de Lange syndrome, it seems likely that additional mechanisms are needed to fine tune interphase adherin and cohesin activity. References 1. Cummings, W.J., Merino, S.T., Young, K.G., Li, L., Johnson, C.W., Sierra, E.A., and Zolan, M.E. (2002). The Coprinus cinereus adherin Rad9 functions in Mre11-dependent DNA repair, meiotic sisterchromatid cohesion, and meiotic homolog pairing. Proc. Natl. Acad. Sci. USA 99, 14958-14963. 2. Furuya, K., Takahashi, K., and Yanagida, M. (1998). Faithful anaphase is ensured by mis4, a sister chromatid cohesion molecule required in S phase and not destroyed in G1 phase. Genes Dev. 12, 3408-3418. 3. Michaelis C, Ciosk, R., and Nasmyth, K. (1997). Cohesins: chromosomal proteins that prevent premature separation of sister chromatids. Cell 91, 35-45. 4. Rollins, R.A., Korom, M., Aulner, N., Martens, A., and Dorsett, D. (2004). Drosophila Nipped-B protein supports sister chromatid cohesion and opposes the Stromalin/Scc3 cohesion factor to facilitate long-range activation of the cut gene. Mol. Cell. Biol. 24, 31003111. 5. Rollins, R.A., Morcillo, P., and Dorsett, D. (1999). Nipped-B, a Drosophila homologue of chromosomal adherins participates in activation by remote enhancers in the cut and Ultrabithorax genes. Genetics 152, 577-593. 6. Gillespie, P.J., and Hirano, T. (2004). Scc2 couples replication licensing to sister chromatid cohesion in Xenopus egg extracts. Curr. Biol., September 7 issue. 7. Krantz, I.D., McCallum, J., DeScipio, C., Kaur, M., Gillis, L.A., Yaeger, D., Jukovsky, L., Wassarman, N., Bottani, A,. Morris, C.A., et al. (2004). Cornelia de Lange syndrome is caused by mutations in NIPBL, the human homolog of the Drosophila Nipped-B gene. Nat. Genet. 36, 631-635. 8. Tonkin, E.T., Wang, T.J., Lisgo, S., Bamshad, M.J., and Strachan, T. (2004). NIPBL, encoding a homolog of fungal Scc2-type sister chromatid cohesion proteins and fly Nipped-B, is mutated in Cornelia de Lange syndrome. Nat. Genet. 36, 636-641. 9. Neuwald, A.F., and Hirano, T. (2000). HEAT repeats associated with condensins, cohesins, and other complexes involved in chromosome-related functions. Genome Res. 10, 1445-1452. 10. Ciosk, R., Shirayama, M., Shevchenko, A., Tanaka, T., Toth, A., Shevchenko, A., Nasmyth, K. (2000). Cohesin's binding to chromosomes depends on a separate complex consisting of Scc2 and Scc4 proteins. Mol. Cell 5, 243-254. 11. Tomonaga, T., Nagao, K., Kawasaki, Y., Furuya, K., Murakami, A., Morishita, J., Yuasa, T., Sutani, T., Kearsey, S.E., Uhlmann, F., et al. (2000). Characterization of fission yeast cohesin: essential anaphase proteolysis of Rad21 phosphorylated in the S phase. Genes Dev. 14, 2757-2570.
12.
13.
14.
15. 16. 17.
18.
19.
20.
Hagstrom, K.A., and Meyer, B.J. (2003). Condensin and cohesin: more than chromosome compactor and glue. Nat. Rev. Genet. 4, 520-534. Glynn, E.F., Megee, P.C., Yu, H.G., Mistrot, C., Unal, E,. Koshland, D.E., DeRisi, J.L., and Gerton, J.L. (2004). Genome-wide mapping of the cohesin complex in the yeast Saccharomyces cerevisiae. PLoS Biol. 2, e259. Lengronne, A., Katou, Y., Mori, S., Yokobayahi, S., Kelly, G.P., Itoh, T., Watanabe, Y., Shirahige, K., and Uhlmann, F. (2004). Cohesin relocation from sites of chromosomal loading to places of convergent transcription. Nature 430, 573-578. Gruber, S., Haering, C.H., and Nasmyth, K. (2003). Chromosomal cohesin forms a ring. Cell 112, 765-777. Milutinovich, M., and Koshland, D.E. (2003). SMC complexes — wrapped up in controversy. Science 300, 1101-1102. Arumugam, P., Gruber, S., Tanaka, K., Haering, C.H., Mechtler, K., and Nasmyth, K. (2003). ATP hydrolysis is required for cohesin's association with chromosomes. Curr. Biol. 13, 1941-1953. Weitzer, S., Lehane, C., and Uhlmann, F. (2003). A model for ATP hydrolysis-dependent binding of cohesin to DNA. Curr. Biol. 13, 1930-1940. Takahashi, T.S., Yiu, P., Chou, M.F., Gygi, S., and Walter, J.C. (2004). Pre-replication complex-dependent recruitment of Xenopus Scc2 and cohesin to chromatin. Nat. Cell. Biol. DOI 10.1038/ncb1177. Kim, J.S., Krasieva, T.B., LaMorte, V., Taylor, A.M., and Yokomori, K. (2002). Specific recruitment of human cohesin to laser-induced DNA damage. J. Biol. Chem. 277, 45149-45153.
Dispatch
Adherin: Key to the Cohesin Ring and Cornelia de Lange Syndrome Dale Dorsett
Adherin facilitates sister chromatid cohesion, DNA repair and binding of the cohesin complex to chromosomes. New studies indicate that adherin activity is coordinated with DNA replication and chromosome segregation, and that its dosage is critical for gene expression and human development.
A recent flurry of papers provides new insights into how the adherin proteins (Table 1) regulate diverse chromosomal functions and development. Adherin functions were originally revealed by genetic mutations in fungi: the rad9-1 adherin mutant of the mushroom Coprinus cinereus is defective in meiotic DNA repair, chromatid cohesin and homolog pairing [1]; mis4 adherin mutants of the fission yeast Schizosaccharomyces pombe display DNA repair and mitotic sister chromatid cohesion defects [2]; and scc2 adherin mutations in the budding yeast Saccharomyces cerevisiae disrupt mitotic chromatid cohesion [3]. A number of new papers report evidence that the chromosome cohesion function of adherin is conserved in higher organisms. Rollins et al. [4] found Drosophila Nipped-B adherin mutations, which reduce transcriptional activation of homeotic genes by distant enhancer sequences [5], also cause cohesion defects. Gillespie and Hirano [6] have shown that depletion of both isoforms of the Xenopus adherin XScc2 from egg extracts blocks cohesion. And in a dramatic development, Krantz et al. [7] and Tonkin et al. [8] report that human NIPBL adherin mutations cause Cornelia de Lange syndrome, which affects many aspects of physical and mental growth. The adherins of different organisms are homologous and contain several HEAT repeats, protein interaction motifs which are conserved in spacing and position [9]. A key question is whether the diverse roles of adherins in cohesion, DNA repair, gene expression and development reflect a single function, or multiple different mechanisms. The known adherin function is to facilitate chromosomal binding of the cohesin protein complex that holds sister chromatids together [10,11]. Cohesin is one of many ‘structural maintenance of chromosome’ (SMC) complexes, conserved in overall structure from bacteria to man, which play diverse roles in chromosome architecture and function (reviewed in [12]). Cohesin consists of Smc1, Smc3, Rad21 (Mcd1/Scc1) and Scc3 (Stromalin) subunits (Figure 1). Smc1 and Smc3 interact to form a V-like structure with two ATPase head domains, and Rad21 interacts with both ATPase domains to form a ring-like Edward A. Doisy Department of Biochemistry and Molecular Biology, Saint Louis University School of Medicine, Saint Louis, Missouri 63104, USA.
structure. In budding yeast, cohesin binds every 10 kilobases or so along the chromosomes, preferring regions between convergent transcription units [13,14]. An attractive model for cohesion is that the cohesin ring encircles DNA so that subsequent replication captures the two sister chromatids within the ring [15] (Figure 1). Other possibilities include a ‘snap’ model in which two cohesin rings bound to the two sister chromatids loop through each other [16]. In either case, establishing cohesion requires opening of the cohesin ring. ATP hydrolysis mutations in the cohesin ATPase domains and scc2 adherin mutations have the same effect: cohesin rings form but fail to bind to chromosomes [17,18]. This raises the idea that adherins stimulate ATP hydrolysis and ring opening [17] (Figure 1). Small amounts of cohesin subunits co-purify with the Scc2/Scc4 adherin complex, indicating that adherin acts directly on cohesin [17]. Recent chromatin immunoprecipitation experiments with scc2 mutants by Lengronne et al. [14] support this idea, because they indicate that cohesin loads at adherin binding sites and translocates away (Figure 1). Recent experiments with Xenopus egg extracts by Gillespie and Hirano [6] and Takahashi et al. [19] indicate that binding of adherins to chromosomes is regulated to coordinate sister chromatid cohesion and DNA replication (Figure 1). Both groups found that geminin inhibition of Cdt1, an essential component of the pre-replication complex that binds origins of DNA replication, reduced chromosomal association of the XScc2 adherin and cohesin. Moreover, depletion of the XOrc1 component of the origin recognition complex [6,19] or the Mcm2–7 complex that licenses origins [19], also blocked adherin binding. In contrast, blocking initiation of DNA replication or origin unwinding with p21CIP1 [6] or p27Kip [19] had no detectable effect on binding of adherin and cohesin to chromatin. Dissociation of adherin from chromatin in prophase was blocked by depletion of the cdc2 mitotic kinase, while depletion of polo-like and aurora B kinases, required for prophase dissociation of cohesin, had no effect on adherin binding [6]. It remains to be seen if the protein complexes that bind to replication origins Table 1. Adherins and their functions. Organism
Adherin
Demonstrated functions
C. cinereus
Rad9
Meiotic DNA repair, chromatid cohesion, homolog pairing
S. pombe
Mis4
Mitotic sister chromatid cohesion, DNA repair
S. cerevisiae
Scc2
Mitotic sister chromatid cohesion
Drosophila
Nipped-B Long-range gene activation, sister chromatid cohesion
Xenopus
XScc2A,B Mitotic sister chromatid cohesion
H. sapiens
NIPBL-A,B Physical and mental development
Current Biology R835
Figure 1. Proposed mechanisms for binding of adherin and cohesin to chromosomes. Recent work indicates that licensing of DNA replication origins, which involves binding of the origin recognition complex (ORC), Cdt1, and the Mcm2–7 complex, stimulates chromosomal binding of adherin by an unknown mechanism [6,19]. Adherin is proposed to stimulate ATP hydrolysis and opening of the cohesin ring to facilitate entry of the chromosome into the cohesin ring [17]. Subsequent DNA replication would trap both sister chromatids in the cohesin ring. From the opposing effects of adherin and cohesin on gene expression, it is proposed that adherin also facilitates localized or temporary removal of cohesin to allow long-range gene activation [4]. Prophase removal of adherin from chromosomes is stimulated by cdc2 mitotic kinase, but not by polo-like kinase or aurora B kinase, which are required for prophase cohesin removal [6].
Mcm2-7
Replication origin licensing adherin binding
Adherin ORC
Cdt1
Cohesin Rad21/Mcd1/Scc1
Stromalin/Scc3 ADP+Pi
Smc1+Smc3 ATP
Cohesin loading
DNA replication
ADP+Pi
Localized cohesin removal gene activation
Prophase adherin and cohesin removal
Polo-like kinase aurora B
ATP
Cdc2
Current Biology
directly recruit adherin, or if formation of originbinding complexes initiates a signal that alters the ability of adherin to bind to chromatin. In addition to sister chromatid cohesion, chromosomal loading of cohesin by adherins can also explain their role in DNA repair. Human cohesin is recruited to sites of DNA damage, and this recruitment depends on Mre11, a critical component of a complex that binds chromosome breaks and is required for recombination and repair [20]. The mushroom adherin Rad9 functions in an Mre11-dependent repair pathway [1]. So beyond fulfilling a basic requirement for chromatid juxtaposition for repair, it seems likely that adherins load additional cohesin at DNA damage sites. The recent experiments by Rollins et al. [4] raise the possibility that adherin may remove cohesin from chromosomes to facilitate gene expression. The Drosophila adherin Nipped-B facilitates long-range activation of the cut and Ultrabithorax homeotic genes by distant transcriptional enhancers in a dosagesensitive manner [5]. Partial reduction of Nipped-B function reduces activation of these genes, while
complete loss of Nipped-B function causes cohesion defects [4,5]. Surprisingly, Nipped-B and cohesin have opposing effects on gene expression, and partial reduction of cohesin subunits increased cut activation without causing cohesion defects [4]. This dichotomy can be explained if cohesin blocks enhancer–promoter interactions, and Nipped-B facilitates activation by removing cohesin. If adherin opens the cohesin ring, this could aid both cohesin loading and removal of cohesin from chromosomes (Figure 1). There may be a steady state between chromosomal and extra-chromosomal cohesin, with the adherin level determining the on–off rates and opportunities for gene activation. It is also possible, however, that cohesin inhibits gene expression by preventing adherin from performing another task that supports activation. Dissecting the roles of adherin and cohesin in gene activation will be critical for understanding Cornelia de Lange syndrome, which displays a variety of developmental deficiencies, including growth, upper limb, cardiac, gastroesophageal and learning defects.
Dispatch R836
Krantz et al. [7] and Tonkin et al. [8] showed that this syndrome, which occurs as frequently as once per 10,000 births, is caused by spontaneous loss-offunction mutations in one copy of the human NIPBL adherin gene. Because the developmental symptoms are caused by reduced adherin dosage, they likely reflect gene expression changes as opposed to cohesion or repair defects. Indeed, effects on homeotic gene expression similar to those caused by partial loss of Drosophila adherin might explain many features of Cornelia de Lange syndrome, such as upper limb abnormalities. The Xenopus egg studies by Gillespie and Hirano [6] and Takahashi et al. [19] show that the binding and removal of adherin to and from chromosomes are coordinated with replication origin licensing and mitotic entry, which ensures that cohesion and loss of cohesion are properly synchronized with DNA replication and chromosome segregation. This also means, however, that cohesin is bound to chromosomes throughout interphase. Given the sensitivity of homeotic gene expression to small changes in adherin and cohesin dosage, and the devastating developmental consequences of such changes as evidenced by Cornelia de Lange syndrome, it seems likely that additional mechanisms are needed to fine tune interphase adherin and cohesin activity. References 1. Cummings, W.J., Merino, S.T., Young, K.G., Li, L., Johnson, C.W., Sierra, E.A., and Zolan, M.E. (2002). The Coprinus cinereus adherin Rad9 functions in Mre11-dependent DNA repair, meiotic sisterchromatid cohesion, and meiotic homolog pairing. Proc. Natl. Acad. Sci. USA 99, 14958-14963. 2. Furuya, K., Takahashi, K., and Yanagida, M. (1998). Faithful anaphase is ensured by mis4, a sister chromatid cohesion molecule required in S phase and not destroyed in G1 phase. Genes Dev. 12, 3408-3418. 3. Michaelis C, Ciosk, R., and Nasmyth, K. (1997). Cohesins: chromosomal proteins that prevent premature separation of sister chromatids. Cell 91, 35-45. 4. Rollins, R.A., Korom, M., Aulner, N., Martens, A., and Dorsett, D. (2004). Drosophila Nipped-B protein supports sister chromatid cohesion and opposes the Stromalin/Scc3 cohesion factor to facilitate long-range activation of the cut gene. Mol. Cell. Biol. 24, 31003111. 5. Rollins, R.A., Morcillo, P., and Dorsett, D. (1999). Nipped-B, a Drosophila homologue of chromosomal adherins participates in activation by remote enhancers in the cut and Ultrabithorax genes. Genetics 152, 577-593. 6. Gillespie, P.J., and Hirano, T. (2004). Scc2 couples replication licensing to sister chromatid cohesion in Xenopus egg extracts. Curr. Biol., September 7 issue. 7. Krantz, I.D., McCallum, J., DeScipio, C., Kaur, M., Gillis, L.A., Yaeger, D., Jukovsky, L., Wassarman, N., Bottani, A,. Morris, C.A., et al. (2004). Cornelia de Lange syndrome is caused by mutations in NIPBL, the human homolog of the Drosophila Nipped-B gene. Nat. Genet. 36, 631-635. 8. Tonkin, E.T., Wang, T.J., Lisgo, S., Bamshad, M.J., and Strachan, T. (2004). NIPBL, encoding a homolog of fungal Scc2-type sister chromatid cohesion proteins and fly Nipped-B, is mutated in Cornelia de Lange syndrome. Nat. Genet. 36, 636-641. 9. Neuwald, A.F., and Hirano, T. (2000). HEAT repeats associated with condensins, cohesins, and other complexes involved in chromosome-related functions. Genome Res. 10, 1445-1452. 10. Ciosk, R., Shirayama, M., Shevchenko, A., Tanaka, T., Toth, A., Shevchenko, A., Nasmyth, K. (2000). Cohesin's binding to chromosomes depends on a separate complex consisting of Scc2 and Scc4 proteins. Mol. Cell 5, 243-254. 11. Tomonaga, T., Nagao, K., Kawasaki, Y., Furuya, K., Murakami, A., Morishita, J., Yuasa, T., Sutani, T., Kearsey, S.E., Uhlmann, F., et al. (2000). Characterization of fission yeast cohesin: essential anaphase proteolysis of Rad21 phosphorylated in the S phase. Genes Dev. 14, 2757-2570.
12.
13.
14.
15. 16. 17.
18.
19.
20.
Hagstrom, K.A., and Meyer, B.J. (2003). Condensin and cohesin: more than chromosome compactor and glue. Nat. Rev. Genet. 4, 520-534. Glynn, E.F., Megee, P.C., Yu, H.G., Mistrot, C., Unal, E,. Koshland, D.E., DeRisi, J.L., and Gerton, J.L. (2004). Genome-wide mapping of the cohesin complex in the yeast Saccharomyces cerevisiae. PLoS Biol. 2, e259. Lengronne, A., Katou, Y., Mori, S., Yokobayahi, S., Kelly, G.P., Itoh, T., Watanabe, Y., Shirahige, K., and Uhlmann, F. (2004). Cohesin relocation from sites of chromosomal loading to places of convergent transcription. Nature 430, 573-578. Gruber, S., Haering, C.H., and Nasmyth, K. (2003). Chromosomal cohesin forms a ring. Cell 112, 765-777. Milutinovich, M., and Koshland, D.E. (2003). SMC complexes — wrapped up in controversy. Science 300, 1101-1102. Arumugam, P., Gruber, S., Tanaka, K., Haering, C.H., Mechtler, K., and Nasmyth, K. (2003). ATP hydrolysis is required for cohesin's association with chromosomes. Curr. Biol. 13, 1941-1953. Weitzer, S., Lehane, C., and Uhlmann, F. (2003). A model for ATP hydrolysis-dependent binding of cohesin to DNA. Curr. Biol. 13, 1930-1940. Takahashi, T.S., Yiu, P., Chou, M.F., Gygi, S., and Walter, J.C. (2004). Pre-replication complex-dependent recruitment of Xenopus Scc2 and cohesin to chromatin. Nat. Cell. Biol. DOI 10.1038/ncb1177. Kim, J.S., Krasieva, T.B., LaMorte, V., Taylor, A.M., and Yokomori, K. (2002). Specific recruitment of human cohesin to laser-induced DNA damage. J. Biol. Chem. 277, 45149-45153.