MARIA A. SCHUMACHER, Ph.D.
Associate Professor

Department of Biochemistry and Molecular Biology
Room: S7.8336B
Telephone: 713-834-6392
e-mail: maschuma@mdanderson.org

Research interests

• X-ray crystallography
• transcription initiation
• transcription regulation
• partition
• DNA segregation
• cell division

The Schumacher laboratory focuses on understanding, at a detailed atomic level, several key biological processes involving protein-nucleic acid interactions. Our major area of interest is DNA segregation. Ultimately, we wish to obtain structural snapshots of every step of DNA segregation using plasmid partition loci as model systems. In addition, we study several proteins that regulate cohesin removal during anaphase in higher organisms. Finally, we examine several global effectors of transcription in both eukaryotes and prokaryotes to understand their mechanism of transcription activation or repression.

The faithful inheritance of genetic information from parent to offspring is essential for the survival of all cells. Deregulation of this process can have profound effects including the development of aneuploidy, which can lead to cancer. Our goal is to understand the basic molecular principles behind this process. DNA segregation involves the directed movement and positioning of chromosomes, which accurately distributes them to their daughter cells at cell division. This process is mediated by functionally homologous par systems in prokaryotic plasmid systems. The simplicity of plasmid partition systems makes them excellent model systems to address the molecular mechanisms of DNA segregation at a detailed atomic level. Indeed, these systems require only three components: a cis-acting centromere DNA site(s) and two trans-acting proteins, a motor protein and a centromere-binding protein. In the first step of partition, multiple centomere-binding proteins bind cooperatively to the centromere-site, which generally consists of several tandem repeats, to form a higher order protein-DNA structure called a segrosome. This structure serves as the assembly site for the motor protein, which then mediates DNA separation of paired, replicated plasmids. There are two major par systems, those that use actin like motor proteins and those that employ Walker type ATPase proteins. We are examining partition by both systems, including the P1 plasmid par system and the multidrug resistant pSK41 par system. Our studies on the P1 system have provided structures of the centomere-binding protein, ParB, bound to minimal centromere elements. These structures have revealed that ParB is a novel DNA-binding protein. Its bridging and pairing capabilities explain how it binds its complex centromere and mediate plasmid pairing. We also recently obtained the first structure of a segrosome, that of the pSK41 ParR-centomere complex. This structure showed that the segrosome is a very large superhelical protein-nucleic acid structure with dimensions ideal for capturing the actin-like filaments recently shown to be formed by the motor ATPase protein. Our structures and biochemical analyses on both centromere-binding and motor proteins and their complexes will provide the foundation for understanding basic molecular mechanisms of how proteins and multiprotein-DNA complexes such as the segrosome, function to mediate and drive plasmid/chromosome segregation.

In our studies of transcription one area of interest is the mechanism of transcription initiation by the primitive eukaryote, T. vaginalis. The transcription start sites of nearly all T. vaginalis genes contain an Inr element that appears to be primarily responsible for start site selection and is recognized by one protein, the Initiator Binding Protein, 39 kDa, IBP39. Thus, compared to higher eukaryotes, T. vaginalis, which is considered the earliest extant eukaryote, provides a simplified model system to study transcription start site selection. IBP39 shows no sequence similarity to any protein and consists of a N-terminal, 14.5 kDa, Inr binding domain (IBD) connected by a long, flexible linker to a C-domain of previously unknown function. Our structural and biochemical studies revealed the basis for recognition of the short and loose consensus Inr sequence by IBP39 and also demonstrated that the C-domain is involved in recruitment of the RNA Polymerase II C-terminal domain (CTD). This recruitment likely explains its role in mediating transcription initiation. Subsequent structural studies aimed at obtaining multi-protein core promoter complexes that possibly include the T. vaginalis RNA Polymerase II are envisioned.


Recent selected publications

• Schumacher MA, Glover TC, Brzoska AJ, Jensen SO, Dunhman TD, Skurray RA, Firth N (2007) Segrosome structure revealed by a complex of ParR with centromere DNA. Nature 450: 1268–1271.
  
  
• Schumacher MA (2007) Structural biology of plasmid segregation proteins. Curr Opin Struct Biol 17: 103–109.
  
  
• Schumacher MA, Mansoor A, Funnell BE (2007) Structure of a four way bridged ParB-DNA complex provides insight into P1 segrosome assembly. J Biol Chem 282: 10456–10464.
  
  
• Schumacher MA, Karamooz E, Zikova A, Trantirek L, Lukes J (2006) Crystal structures of T. brucei MRP1/MRP2 guide-RNA-binding complex Reveals RNA matchmaking mechanism. Cell 126:701–711.
  
  
• Schumacher MA, Funnell BE (2005) ParB-DNA structures reveal mechanism of partition complex formation. Nature 438: 516–519.
  
  
• Schumacher MA, Allen GS, Diel M, Deidel G, Hillen W, Brennan RG (2004) Structural basis for allosteric control of the transcription regulator CcpA by the phosphoprotein HPr-Ser46-P. Cell 118: 731–741.
  
  
• Schumacher MA, Crum M, Miller M (2004) Crystal structure of apocalmodulin and an apocalmodulin/SK2 CaMBD complex: mechanism of Ca2+-activated SK channel gating. Structure 12: 849–860.
  
  
• Schumacher MA, Lau AOT, Johnson PJ (2003) Structural basis of core promoter recognition in a primitive Eukaryote. Cell 115: 413–424.
  
  
• Schumacher MA, Rivard A F, Bachinger HP, Adelman JP (2001) Structure of the gating domain of a Ca2+-activated K+ channel complexed with Ca2+/calmodulin. Nature 410: 1120–1124.
  
  
• Schumacher MA, Miller MC, Grkovic S, Brown MH, Skurray RA, Brennan RG (2001) Structural mechanisms of QacR induction and multidrug recognition. Science 294: 2158–2163.

---

Mailing Address:
Department of Biochemistry and Molecular Biology, Unit 1000
U.T. M.D. Anderson Cancer Center
1515 Holcombe Boulevard
Houston, TX 77030

转载本文请联系原作者获取授权，同时请注明本文来自徐文科学网博客。
链接地址：https://m.sciencenet.cn/blog-200233-216415.html

上一篇：试论蛮不讲理与不讲人情
下一篇：Nature杂志上的一期Article很特别