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 Department of Biophysics
Search Biophysics JHU

Thomas C. Jenkins
Department of Biophysics
110 Jenkins Hall
3400 N. Charles Street
Baltimore, MD 21218

Dr. Bertrand Garcia-Moreno E.
Department Chair

410-516-7245 phone
410-516-4118 fax

 

Dr. Gregory Bowman
Associate Professor, Biophysics

Johns Hopkins University
Department of Biophysics
3400 North Charles Street
Baltimore, MD 21218
410-516-7850 Office
410-516-4118 Fax
gdbowman@jhu.edu
Lab Home Page

  

Nearly all cells in the human body possess the same set of genes, yet only a subset of these genes are turned “on” in any particular tissue. Tight control over which genes are “on” and “off” is intimately tied to the physical packaging of chromosomes, called chromatin structure. The continuous compaction and decondensation in chromosomal packaging is known as chromatin remodeling, a process driven by the covalent modification and physical movement of nucleosomes, the basic repeating unit of chromatin. Given that disruptions of normal gene regulation can result in cancer and developmental disorders, a molecular understanding of chromatin remodeling will allow for development of novel therapeutics that target chromatin as a means of blocking uncontrolled cell growth.

Chromatin remodelers are multicomponent protein machines that assemble, move and evict nucleosomes from DNA. The central “motor” for all remodelers is a conserved helicase-like ATPase that serves as a DNA translocase. Elegant footprinting studies from the labs of Blaine Bartholomew and Carl Wu have revealed that remodelers contact nucleosomal DNA in several distinct locations, and it is now well established that the core ATPase module translocates along nucleosomal DNA at an internal site. While the translocation of the ATPase module presumably disrupts histone-DNA contacts as a first step in sliding nucleosomes, it is not clear how this translocase-activity promotes movement of DNA around the histone core. In addition, it is not clear how the auxiliary (non-ATPase) domains participate in the remodeling reaction.

Despite tantilizing biochemical information, the three-dimensional architecture of chromatin remodelers is not known and it has therefore not been possible to determine what structural changes remodelers might undergo and how such changes drive the remodeling process. Our long-term goal is to establish a biochemical and biophysical framework necessary for describing and understanding the process of chromatin remodeling. We are focused on a monomeric chromatin remodeler called Chd1, which possesses three regions sufficient for remodeling: two N-terminal chromodomains, a central ATPase module, and a C-terminal DNA-binding region. Our strategy is to obtain high-resolution structural information using X-ray crystallography, and couple this information to biochemical studies we are performing with Chd1 variants. We have solved crystal structures of the chromodomain-ATPase portion, and also separately, the DNA-binding domain of Chd1, which have suggested mechanisms for regulating the nucleosome sliding cycle. In addition, we have recently discovered that foreign, sequence-specific DNA-binding domains can functionally replace the native DNA-binding domain, and allow the remodeler to move nucleosomes in a sequence-dependent fashion.

Selected Publications:

  • Sharma, A., Jenkins, K.R., Héroux, A., Bowman, G.D. (2011) Crystal Structure of the Chromodomain Helicase DNA-Binding Protein 1 (Chd1) DNA-Binding Domain in Complex with DNA. J Biol Chem. 286 (49):42099-104.
  • Patel, A., McKnight, J.N., Genzor, P., Bowman, G.D. (2011) Identification of Residues in Chromodomain Helicase DNA-Binding Protein 1 (Chd1) Required for Coupling ATP Hydrolysis to Nucleosome Sliding. J Biol Chem. 286 (51):43984-93.
  • Hauk, G,. Bowman, G.D. (2011) Structural Insights into Regulation and Action of SWI2/SNF2 ATPases. Curr Opin Struct Biol. 21(6):719-27.
  • McKnight J.N., Jenkins, K.R., Nodelman I.M., Escobar T., Bowman, G.D. (2011) Extranucleosomal DNA Binding Directs Nucleosome Sliding By Chd1. Mol. Cell Biol. 31(23):4746-59.
  • Hauk*, G,. McKnight*, J., Nodelman, I.M., Bowman, G.D. (2010) The Chromodomains of the Chd1 Chromatin Remodeler Regulate DNA Access to the ATPase Motor. Mol Cell. 39(5):711-23. (* equal contribution)
  • Sczepanski, J.T., Wong, R.S., McKnight, J.N., Bowman, G.D., Greenberg, M.M. (2010) Rapid DNA-protein cross-linking and strand scission by an abasic site in a nucleosome core particle. Proc Natl Acad Sci U S A. 107(52):22475-80.
  • Bowman, G.D. (2010)  Mechanisms of ATP-dependent nucleosome sliding. Curr. Opin. Struct. Biol. 20:73-81.
  • Celedon, A., I.M. Nodelman, B. Wildt, R. Dewan, P. Searson, D. Wirtz, G.D. Bowman, and S.X. Sun. (2009) Magnetic tweezers measurement of single molecule torque. Nano Lett. 9:1720-1725.
 

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