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11 results on '"De Haan, Georgius"'

1. Altered Function of the SCN1A Voltage-gated Sodium Channel Leads to γ-Aminobutyric Acid-ergic (GABAergic) Interneuron Abnormalities*

Author

Martin, Melinda S, Dutt, Karoni, Papale, Ligia A, Dubé, Céline M, Dutton, Stacey B, de Haan, Georgius, Shankar, Anupama, Tufik, Sergio, Meisler, Miriam H, Baram, Tallie Z, Goldin, Alan L, and Escayg, Andrew

Subjects
Genetics, Neurodegenerative, Pediatric, Epilepsy, Neurosciences, Brain Disorders, 2.1 Biological and endogenous factors, Aetiology, Neurological, Animals, Female, Gene Expression Regulation, Homozygote, Interneurons, Male, Mice, Mice, Inbred C57BL, Mice, Transgenic, Mutation, NAV1.1 Voltage-Gated Sodium Channel, Nerve Tissue Proteins, Neurons, Seizures, Sodium Channels, gamma-Aminobutyric Acid, Chemical Sciences, Biological Sciences, Medical and Health Sciences, Biochemistry & Molecular Biology
Abstract

Voltage-gated sodium channels are required for the initiation and propagation of action potentials. Mutations in the neuronal voltage-gated sodium channel SCN1A are associated with a growing number of disorders including generalized epilepsy with febrile seizures plus (GEFS+),(7) severe myoclonic epilepsy of infancy, and familial hemiplegic migraine. To gain insight into the effect of SCN1A mutations on neuronal excitability, we introduced the human GEFS+ mutation SCN1A-R1648H into the orthologous mouse gene. Scn1a(RH/RH) mice homozygous for the R1648H mutation exhibit spontaneous generalized seizures and premature death between P16 and P26, whereas Scn1a(RH/+) heterozygous mice exhibit infrequent spontaneous generalized seizures, reduced threshold and accelerated propagation of febrile seizures, and decreased threshold to flurothyl-induced seizures. Inhibitory cortical interneurons from P5-P15 Scn1a(RH/+) and Scn1a(RH/RH) mice demonstrated slower recovery from inactivation, greater use-dependent inactivation, and reduced action potential firing compared with wild-type cells. Excitatory cortical pyramidal neurons were mostly unaffected. These results suggest that this SCN1A mutation predominantly impairs sodium channel activity in interneurons, leading to decreased inhibition. Decreased inhibition may be a common mechanism underlying clinically distinct SCN1A-derived disorders.

Published
2010

2. Altered function of the SCN1A voltage-gated sodium channel leads to gamma-aminobutyric acid-ergic (GABAergic) interneuron abnormalities.

Author

Martin, Melinda S, Dutt, Karoni, Papale, Ligia A, Dubé, Céline M, Dutton, Stacey B, de Haan, Georgius, Shankar, Anupama, Tufik, Sergio, Meisler, Miriam H, Baram, Tallie Z, Goldin, Alan L, and Escayg, Andrew

Subjects
Neurons, Interneurons, Animals, Mice, Inbred C57BL, Mice, Transgenic, Mice, Seizures, gamma-Aminobutyric Acid, Sodium Channels, Nerve Tissue Proteins, Gene Expression Regulation, Homozygote, Mutation, Female, Male, NAV1.1 Voltage-Gated Sodium Channel, Inbred C57BL, Transgenic, Brain Disorders, Genetics, Neurodegenerative, Epilepsy, Neurosciences, Pediatric, 2.1 Biological and endogenous factors, Neurological, Biological Sciences, Medical and Health Sciences, Chemical Sciences, Biochemistry & Molecular Biology
Abstract

Voltage-gated sodium channels are required for the initiation and propagation of action potentials. Mutations in the neuronal voltage-gated sodium channel SCN1A are associated with a growing number of disorders including generalized epilepsy with febrile seizures plus (GEFS+),(7) severe myoclonic epilepsy of infancy, and familial hemiplegic migraine. To gain insight into the effect of SCN1A mutations on neuronal excitability, we introduced the human GEFS+ mutation SCN1A-R1648H into the orthologous mouse gene. Scn1a(RH/RH) mice homozygous for the R1648H mutation exhibit spontaneous generalized seizures and premature death between P16 and P26, whereas Scn1a(RH/+) heterozygous mice exhibit infrequent spontaneous generalized seizures, reduced threshold and accelerated propagation of febrile seizures, and decreased threshold to flurothyl-induced seizures. Inhibitory cortical interneurons from P5-P15 Scn1a(RH/+) and Scn1a(RH/RH) mice demonstrated slower recovery from inactivation, greater use-dependent inactivation, and reduced action potential firing compared with wild-type cells. Excitatory cortical pyramidal neurons were mostly unaffected. These results suggest that this SCN1A mutation predominantly impairs sodium channel activity in interneurons, leading to decreased inhibition. Decreased inhibition may be a common mechanism underlying clinically distinct SCN1A-derived disorders.

Published
2010

3. A targeted deleterious allele of the splicing factor SCNM1 in the mouse

Author

Howell, Viive M., de Haan, Georgius, Bergren, Sarah, Jones, Julie M., Culiat, Cymbeline T., Michaud, Edward J., Frankel, Wayne N., and Meisler, Miriam H.

Subjects
Allelomorphism -- Identification and classification, Genetic engineering -- Research, Phenotype -- Identification and classification, Sodium channels -- Properties, Biological sciences
Abstract

The auxiliary spliceosomal protein SCNM1 contributes to recognition of nonconsensus splice donor sites. SCNM1 was first identified as a modifier of the severity of a sodium channelopathy in the mouse. The most severely affected strain, C57BL/6J, carries the variant allele SCN[M1.sup.R187TX], which is defective in splicing the mutated donor site in the Scn[8a.sup.medJ] transcript. To further probe the in vivo function of SCNM1, we constructed a floxed allele and generated a mouse with constitutive deletion of exons 3-5. The SCN[M1.sup.[DELTA]3-5] protein is produced and correctly localized to the nucleus, but is more functionally impaired than the C57BL/6J allele. Deficiency of SCNM1 did not significantly alter other brain transcripts. We characterized an ENU-induced allele of Scnm1 and evaluated the ability of wild-type SCNM1 to rescue lethal mutations of I-mfa and Brunol4. The phenotypes of the Scn[ml.sup.[DELTA]3-5] mutant confirm the role of this splice factor in processing the Scn[8a.sup.medJ] transcript and provide a new allele of greater severity for future studies.

Published
2008

5. Evolution of genes and genomes on the Drosophila phylogeny

Author

Clark, Andrew G., Eisen, Michael B., Smith, Douglas R., Bergman, Casey M., Oliver, Brian, Markow, Therese A., Kaufman, Thomas C., Kellis, Manolis, Gelbart, William, Iyer, Venky N., Pollard, Daniel A., Sackton, Timothy B., Larracuente, Amanda M., Singh, Nadia D., Abad, Jose P., Abt, Dawn N., Adryan, Boris, Aguade, Montserrat, Akashi, Hiroshi, Anderson, Wyatt W., Aquadro, Charles F., Ardell, David H., Arguello, Roman, Artieri, Carlo G., Barbash, Daniel A., Barker, Daniel, Barsanti, Paolo, Batterham, Phil, Batzoglou, Serafim, Begun, Dave, Bhutkar, Arjun, Blanco, Enrico, Bosak, Stephanie A., Bradley, Robert K., Brand, Adrianne D., Brent, Michael R., Brooks, Angela N., Brown, Randall H., Butlin, Roger K., Caggese, Corrado, Calvi, Brian R., Bernardo de Carvalho, A., Caspi, Anat, Castrezana, Sergio, Celniker, Susan E., Chang, Jean L., Chapple, Charles, Chatterji, Sourav, Chinwalla, Asif, Civetta, Alberto, Clifton, Sandra W., Comeron, Josep M., Costello, James C., Coyne, Jerry A., Daub, Jennifer, David, Robert G., Delcher, Arthur L., Delehaunty, Kim, Do, Chuong B., Ebling, Heather, Edwards, Kevin, Eickbush, Thomas, Evans, Jay D., Filipski, Alan, Findeiß, Sven, Freyhult, Eva, Fulton, Lucinda, Fulton, Robert, Garcia, Ana C. L., Gardiner, Anastasia, Garfield, David A., Garvin, Barry E., Gibson, Greg, Gilbert, Don, Gnerre, Sante, Godfrey, Jennifer, Good, Robert, Gotea, Valer, Gravely, Brenton, Greenberg, Anthony J., Griffiths-Jones, Sam, Gross, Samuel, Guigo, Roderic, Gustafson, Erik A., Haerty, Wilfried, Hahn, Matthew W., Halligan, Daniel L., Halpern, Aaron L., Halter, Gillian M., Han, Mira V., Heger, Andreas, Hillier, LaDeana, Hinrichs, Angie S., Holmes, Ian, Hoskins, Roger A., Hubisz, Melissa J., Hultmark, Dan, Huntley, Melanie A., Jaffe, David B., Jagadeeshan, Santosh, Jeck, William R., Johnson, Justin, Jones, Corbin D., Jordan, William C., Karpen, Gary H., Kataoka, Eiko, Keightley, Peter D., Kheradpour, Pouya, Kirkness, Ewen F., Koerich, Leonardo B., Kristiansen, Karsten, Kudrna, Dave, Kulathinal, Rob J., Kumar, Sudhir, Kwok, Roberta, Lander, Eric, Langley, Charles H., Lapoint, Richard, Lazzaro, Brian P., Lee, So-Jeong, Levesque, Lisa, Li, Ruiqiang, Lin, Chiao-Feng, Lin, Michael F., Lindblad-Toh, Kerstin, Llopart, Ana, Long, Manyuan, Low, Lloyd, Lozovsky, Elena, Lu, Jian, Luo, Meizhong, Machado, Carlos A., Makalowski, Wojciech, Marzo, Mar, Matsuda, Muneo, Matzkin, Luciano, McAllister, Bryant, McBride, Carolyn S., McKernan, Brendan, McKernan, Kevin, Mendez-Lago, Maria, Minx, Patrick, Mollenhauer, Michael U., Montooth, Kristi, Mount, Stephen M., Mu, Xu, Myers, Eugene, Negre, Barbara, Newfeld, Stuart, Nielsen, Rasmus, Noor, Mohamed A. F., O'Grady, Patrick, Pachter, Lior, Papaceit, Montserrat, Parisi, Matthew J., Parisi, Michael, Parts, Leopold, Pedersen, Jakob S., Pesole, Graziano, Phillippy, Adam M., Ponting, Chris P., Pop, Mihai, Porcelli, Damiano, Powell, Jeffrey R., Prohaska, Sonja, Pruitt, Kim, Puig, Marta, Quesneville, Hadi, Ravi Ram, Kristipati, Rand, David, Rasmussen, Matthew D., Reed, Laura K., Reenan, Robert, Reily, Amy, Remington, Karin A., Rieger, Tania T., Ritchie, Michael G., Robin, Charles, Rogers, Yu-Hui, Rohde, Claudia, Rozas, Julio, Rubenfield, Marc J., Ruiz, Alfredo, Russo, Susan, Salzberg, Steven L., Sanchez-Gracia, Alejandro, Saranga, David J., Sato, Hajime, Schaeffer, Stephen W., Schatz, Michael C., Schlenke, Todd, Schwartz, Russell, Segarra, Carmen, Singh, Rama S., Sirot, Laura, Sirota, Marina, Sisneros, Nicholas B., Smith, Chris D., Smith, Temple F., Spieth, John, Stage, Deborah E., Stark, Alexander, Stephan, Wolfgang, Strausberg, Robert L., Strempel, Sebastian, Sturgill, David, Sutton, Granger, Sutton, Granger G., Tao, Wei, Teichmann, Sarah, Tobari, Yoshiko N., Tomimura, Yoshihiko, Tsolas, Jason M., Valente, Vera L. S., Venter, Eli, Craig Venter, J., Vicario, Saverio, Vieira, Filipe G., Vilella, Albert J., Villasante, Alfredo, Walenz, Brian, Wang, Jun, Wasserman, Marvin, Watts, Thomas, Wilson, Derek, Wilson, Richard K., Wing, Rod A., Wolfner, Mariana F., Wong, Alex, Ka-Shu Wong, Gane, Wu, Chung-I, Wu, Gabriel, Yamamoto, Daisuke, Yang, Hsiao-Pei, Yang, Shiaw-Pyng, Yorke, James A., Yoshida, Kiyohito, Zdobnov, Evgeny, Zhang, Peili, Zhang, Yu, Zimin, Aleksey V., Baldwin, Jennifer, Abdouelleil, Amr, Abdulkadir, Jamal, Abebe, Adal, Abera, Brikti, Abreu, Justin, Christophe Acer, St, Aftuck, Lynne, Alexander, Allen, An, Peter, Anderson, Erica, Anderson, Scott, Arachi, Harindra, Azer, Marc, Bachantsang, Pasang, Barry, Andrew, Bayul, Tashi, Berlin, Aaron, Bessette, Daniel, Bloom, Toby, Blye, Jason, Boguslavskiy, Leonid, Bonnet, Claude, Boukhgalter, Boris, Bourzgui, Imane, Brown, Adam, Cahill, Patrick, Channer, Sheridon, Cheshatsang, Yama, Chuda, Lisa, Citroen, Mieke, Collymore, Alville, Cooke, Patrick, Costello, Maura, D'Aco, Katie, Daza, Riza, De Haan, Georgius, DeGray, Stuart, DeMaso, Christina, Dhargay, Norbu, Dooley, Kimberly, Dooley, Erin, Doricent, Missole, Dorje, Passang, Dorjee, Kunsang, Dupes, Alan, Elong, Richard, Falk, Jill, Farina, Abderrahim, Faro, Susan, Ferguson, Diallo, Fisher, Sheila, Foley, Chelsea D., Franke, Alicia, Friedrich, Dennis, Gadbois, Loryn, Gearin, Gary, Gearin, Christina R., Giannoukos, Georgia, Goode, Tina, Graham, Joseph, Grandbois, Edward, Grewal, Sharleen, Gyaltsen, Kunsang, Hafez, Nabil, Hagos, Birhane, Hall, Jennifer, Henson, Charlotte, Hollinger, Andrew, Honan, Tracey, Huard, Monika D., Hughes, Leanne, Hurhula, Brian, Erii Husby, M, Kamat, Asha, Kanga, Ben, Kashin, Seva, Khazanovich, Dmitry, Kisner, Peter, Lance, Krista, Lara, Marcia, Lee, William, Lennon, Niall, Letendre, Frances, LeVine, Rosie, Lipovsky, Alex, Liu, Xiaohong, Liu, Jinlei, Liu, Shangtao, Lokyitsang, Tashi, Lokyitsang, Yeshi, Lubonja, Rakela, Lui, Annie, MacDonald, Pen, Magnisalis, Vasilia, Maru, Kebede, Matthews, Charles, McCusker, William, McDonough, Susan, Mehta, Teena, Meldrim, James, Meneus, Louis, Mihai, Oana, Mihalev, Atanas, Mihova, Tanya, Mittelman, Rachel, Mlenga, Valentine, Montmayeur, Anna, Mulrain, Leonidas, Navidi, Adam, Naylor, Jerome, Negash, Tamrat, Nguyen, Thu, Nguyen, Nga, Nicol, Robert, Norbu, Choe, Norbu, Nyima, Novod, Nathaniel, O'Neill, Barry, Osman, Sahal, Markiewicz, Eva, Oyono, Otero L., Patti, Christopher, Phunkhang, Pema, Pierre, Fritz, Priest, Margaret, Raghuraman, Sujaa, Rege, Filip, Reyes, Rebecca, Rise, Cecil, Rogov, Peter, Ross, Keenan, Ryan, Elizabeth, Settipalli, Sampath, Shea, Terry, Sherpa, Ngawang, Shi, Lu, Shih, Diana, Sparrow, Todd, Spaulding, Jessica, Stalker, John, Stange-Thomann, Nicole, Stavropoulos, Sharon, Stone, Catherine, Strader, Christopher, Tesfaye, Senait, Thomson, Talene, Thoulutsang, Yama, Thoulutsang, Dawa, Topham, Kerri, Topping, Ira, Tsamla, Tsamla, Vassiliev, Helen, Vo, Andy, Wangchuk, Tsering, Wangdi, Tsering, Weiand, Michael, Wilkinson, Jane, Wilson, Adam, Yadav, Shailendra, Young, Geneva, Yu, Qing, Zembek, Lisa, Zhong, Danni, Zimmer, Andrew, Zwirko, Zac, Alvarez, Pablo, Brockman, Will, Butler, Jonathan, Chin, CheeWhye, Grabherr, Manfred, Kleber, Michael, Mauceli, Evan, and MacCallum, Iain

Subjects
Environmental issues, Science and technology, Zoology and wildlife conservation
Abstract

Author(s): Drosophila 12 Genomes Consortium; Project Leaders; Andrew G. Clark (corresponding author) [1]; Michael B. Eisen (corresponding author) [2, 3]; Douglas R. Smith (corresponding author) [4]; Casey M. Bergman (corresponding [...]

Published
2007
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6. Genome of the marsupial Monodelphis domestica reveals innovation in non-coding sequences

Author

Mikkelsen, Tarjei S., Wakefield, Matthew J., Aken, Bronwen, Amemiya, Chris T., Chang, Jean L., Duke, Shannon, Garber, Manuel, Gentles, Andrew J., Goodstadt, Leo, Heger, Andreas, Jurka, Jerzy, Kamal, Michael, Mauceli, Evan, Searle, Stephen M. J., Sharpe, Ted, Baker, Michelle L., Batzer, Mark A., Benos, Panayiotis V., Belov, Katherine, Clamp, Michele, Cook, April, Cuff, James, Das, Radhika, Davidow, Lance, Deakin, Janine E., Fazzari, Melissa J., Glass, Jacob L., Grabherr, Manfred, Greally, John M., Gu, Wanjun, Hore, Timothy A., Huttley, Gavin A., Kleber, Michael, Jirtle, Randy L., Koina, Edda, Lee, Jeannie T., Mahony, Shaun, Marra, Marco A., Miller, Robert D., Nicholls, Robert D., Oda, Mayumi, Papenfuss, Anthony T., Parra, Zuly E., Pollock, David D., Ray, David A., Schein, Jacqueline E., Speed, Terence P., Thompson, Katherine, VandeBerg, John L., Wade, Claire M., Walker, Jerilyn A., Waters, Paul D., Webber, Caleb, Weidman, Jennifer R., Xie, Xiaohui, Zody, Michael C., Baldwin, Jennifer, Abdouelleil, Amr, Abdulkadir, Jamal, Abebe, Adal, Abera, Brikti, Abreu, Justin, Acer, St Christophe, Aftuck, Lynne, Alexander, Allen, An, Peter, Anderson, Erica, Anderson, Scott, Arachi, Harindra, Azer, Marc, Bachantsang, Pasang, Barry, Andrew, Bayul, Tashi, Berlin, Aaron, Bessette, Daniel, Bloom, Toby, Blye, Jason, Boguslavskiy, Leonid, Bonnet, Claude, Boukhgalter, Boris, Bourzgui, Imane, Brown, Adam, Cahill, Patrick, Channer, Sheridon, Cheshatsang, Yama, Chuda, Lisa, Citroen, Mieke, Collymore, Alville, Cooke, Patrick, Costello, Maura, D'Aco, Katie, Daza, Riza, De Haan, Georgius, DeGray, Stuart, DeMaso, Christina, Dhargay, Norbu, Dooley, Kimberly, Dooley, Erin, Doricent, Missole, Dorje, Passang, Dorjee, Kunsang, Dupes, Alan, Elong, Richard, Falk, Jill, Farina, Abderrahim, Faro, Susan, Ferguson, Diallo, Fisher, Sheila, Foley, Chelsea D., Franke, Alicia, Friedrich, Dennis, Gadbois, Loryn, Gearin, Gary, Gearin, Christina R., Giannoukos, Georgia, Goode, Tina, Graham, Joseph, Grandbois, Edward, Grewal, Sharleen, Gyaltsen, Kunsang, Hafez, Nabil, Hagos, Birhane, Hall, Jennifer, Henson, Charlotte, Hollinger, Andrew, Honan, Tracey, Huard, Monika D., Hughes, Leanne, Hurhula, Brian, Husby, M. Erii, Kamat, Asha, Kanga, Ben, Kashin, Seva, Khazanovich, Dmitry, Kisner, Peter, Lance, Krista, Lara, Marcia, Lee, William, Lennon, Niall, Letendre, Frances, LeVine, Rosie, Lipovsky, Alex, Liu, Xiaohong, Liu, Jinlei, Liu, Shangtao, Lokyitsang, Tashi, Lokyitsang, Yeshi, Lubonja, Rakela, Lui, Annie, MacDonald, Pen, Magnisalis, Vasilia, Maru, Kebede, Matthews, Charles, McCusker, William, McDonough, Susan, Mehta, Teena, Meldrim, James, Meneus, Louis, Mihai, Oana, Mihalev, Atanas, Mihova, Tanya, Mittelman, Rachel, Mlenga, Valentine, Montmayeur, Anna, Mulrain, Leonidas, Navidi, Adam, Naylor, Jerome, Negash, Tamrat, Nguyen, Thu, Nguyen, Nga, Nicol, Robert, Norbu, Choe, Norbu, Nyima, Novod, Nathaniel, O'Neill, Barry, Osman, Sahal, Markiewicz, Eva, Oyono, Otero L., Patti, Christopher, Phunkhang, Pema, Pierre, Fritz, Priest, Margaret, Raghuraman, Sujaa, Rege, Filip, Reyes, Rebecca, Rise, Cecil, Rogov, Peter, Ross, Keenan, Ryan, Elizabeth, Settipalli, Sampath, Shea, Terry, Sherpa, Ngawang, Shi, Lu, Shih, Diana, Sparrow, Todd, Spaulding, Jessica, Stalker, John, Stange-Thomann, Nicole, Stavropoulos, Sharon, Stone, Catherine, Strader, Christopher, Tesfaye, Senait, Thomson, Talene, Thoulutsang, Yama, Thoulutsang, Dawa, Topham, Kerri, Topping, Ira, Tsamla, Tsamla, Vassiliev, Helen, Vo, Andy, Wangchuk, Tsering, Wangdi, Tsering, Weiand, Michael, Wilkinson, Jane, Wilson, Adam, Yadav, Shailendra, Young, Geneva, Yu, Qing, Zembek, Lisa, Zhong, Danni, Zimmer, Andrew, Zwirko, Zac, Jaffe, David B., Alvarez, Pablo, Brockman, Will, Butler, Jonathan, Chin, CheeWhye, Gnerre, Sante, MacCallum, Iain, Graves, Jennifer A. Marshall, Ponting, Chris P., Breen, Matthew, Samollow, Paul B., Lander, Eric S., and Lindblad-Toh, Kerstin

Subjects
Environmental issues, Science and technology, Zoology and wildlife conservation
Abstract

Author(s): Tarjei S. Mikkelsen (corresponding author) [1, 2]; Matthew J. Wakefield [3]; Bronwen Aken [4]; Chris T. Amemiya [5]; Jean L. Chang [1]; Shannon Duke [6]; Manuel Garber [1]; Andrew [...]

Published
2007
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8. The ANK3 Bipolar Disorder Gene Regulates Psychiatric-Related Behaviors That Are Modulated by Lithium and Stress

Author

Leussis, Melanie P., primary, Berry-Scott, Erin M., additional, Saito, Mai, additional, Jhuang, Hueihan, additional, de Haan, Georgius, additional, Alkan, Ozan, additional, Luce, Catherine J., additional, Madison, Jon M., additional, Sklar, Pamela, additional, Serre, Thomas, additional, Root, David E., additional, and Petryshen, Tracey L., additional

Published
2013
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11. Prebending the Estrogen Response Element Destabilizes Binding of the Estrogen Receptor DNA Binding Domain

Author

Kim, Jongsook, de Haan, Georgius, Nardulli, Ann M., and Shapiro, David J.

Abstract

Binding of many eukaryotic transcription regulatory proteins to their DNA recognition sequences results in conformational changes in DNA. To test the effect of altering DNA topology by prebending a transcription factor binding site, we examined the interaction of the estrogen receptor (ER) DNA binding domain (DBD) with prebent estrogen response elements (EREs). When the ERE in minicircle DNA was prebent toward the major groove, which is in the same direction as the ER-induced DNA bend, there was no significant effect on ER DBD binding relative to the linear counterparts. However, when the ERE was bent toward the minor groove, in a direction that opposes the ER-induced DNA bend, there was a four- to eightfold reduction in ER DBD binding. Since reduced binding was also observed with the ERE in nicked circles, the reduction in binding was not due to torsional force induced by binding of ER DBD to the prebent ERE in covalently closed minicircles. To determine the mechanism responsible for reduced binding to the prebent ERE, we examined the effect of prebending the ERE on the association and dissociation of the ER DBD. Binding of the ER DBD to ERE-containing minicircles was rapid when the EREs were prebent toward either the major or minor groove of the DNA (konof 9.9 · 106to 1.7 · 107M−1s−1). Prebending the ERE toward the minor groove resulted in an increase in koffof four- to fivefold. Increased dissociation of the ER DBD from the ERE is, therefore, the major factor responsible for reduced binding of the ER DBD to an ERE prebent toward the minor groove. These data provide the first direct demonstration that the interaction of a eukaryotic transcription factor with its recognition sequence can be strongly influenced by altering DNA topology through prebending the DNA.

Published
1997
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