Education

BA (1978) Oberlin College, Biology
PhD (1984) University of Colorado School of Medicine, Microbiology and Immunology
Postdoctoral Fellow (1984-89) Harvard Medical School, Biochemistry

Research Interest

Enzymatic transactions that take place on DNA substrates play an important role not only in controlling gene expression but also in maintaining integrity of the cellular genomes. Central to these processes is the control of molecular recognition, the process by which proteins required for multi-step reactions are recruited to the right place at the right time. Research work in our laboratory focuses on such transactions that take place in two basic cellular processes, the transition from recombination to replication and the recognition of substrates by molecular chaperones and proteases. The former is a process involved in diverse processes such as the replication of transposable elements, double strand break repair, and resumption of stalled replication forks. The latter process plays a critical part in controlling the timing of various cellular events, especially in response to external and physiological signals. These processes are involved in diverse cellular functions such as the maintenance of genome stability, stress response, and tumor suppression.

Two major projects in the laboratory examine the mechanism of such transactions. First, we have examined the replication of a transposon as it moves from one position of the chromosome to another. Upon promoting integration of the element to a new site, the transpososome, which carries out the recombination reaction, is remodeled to a replisome by progressive changes in the nucleoprotein complex assembled at the transposon ends. One of the transition factors is the translation initiation factor 2, which remodels the nucleoprotein assembly such that restart proteins, which promote replication restart, can bind and promote replisome assembly. A second major project examines the regulation of proteolysis by the chaperone-linked protease ClpXP. Substrates that have a degradation tag in the form of a ClpX recognition motif are bound by the the AAA+ domain of ClpX, which unfolds the substrate for proteolysis by ClpP. We have identified a regulable form of the degradation tag and the mechanism for turning it on and off. This degradation tag is activated from a dormant state through conformational changes that induce ligand flexibility. A major goal is to examine how a ClpX substrate with such a regulable recognition motif can act as sensor for signaling molecules and other substances that promote recognition by ClpX to induce a reaction.

Selected Publications

Marshall-Batty, K. R., and H. Nakai. 2008. Activation of a dormant ClpX recognition motif of bacteriophage Mu repressor by inducing high local flexibility. J. Biol. Chem. IN PRESS. PMID: 18230617

Marshall-Batty, K. R., and H. Nakai. 2008. Trans-targeting of protease substrates by conformationally activating a regulable ClpX-recognition motif. Mol. Microbiol. 67:920-933.

North, S. H., S. E. Kirtland, and H. Nakai. 2007. Translation factor IF2 at the interface of transposition and replication by the PriA-PriC pathway. Mol. Microbiol. 66:1566-78.

North, S. H., and H. Nakai. 2005. Host factors that promote transpososome disassembly and the PriA-PriC pathway for restart primosome assembly. Mol. Microbiol. 56:1601-1616.

Chen, H. W., S. H. North, and H. Nakai. 2004. Properties of the PriA helicase domain and its role in binding PriA to specific DNA structures. J. Biol. Chem. 279:38503-12.

Mukhopadhyay, B., K. R. Marshall-Batty, B. D. Kim, D. O'Handley, and H. Nakai. 2003. Modulation of phage Mu repressor DNA binding and degradation by distinct determinants in its C-terminal domain. Mol. Microbiol. 47:171-182.

O'Handley, D., and H. Nakai. 2002. Derepression of bacteriophage Mu transposition functions by truncated forms of the immunity repressor. J. Mol. Biol. 322:311-324.

Rai, S. S., D. O'Handley, and H. Nakai. 2001. Conformational dynamics of a transposition repressor in modulating DNA binding. J. Mol. Biol. 312:311-322.

Rai, S. S., D. O'Handley, and H. Nakai. 2001. Conformational dynamics of a transposition repressor in modulating DNA binding. J. Mol. Biol. 312:311-322.

Jones, J. M., and H. Nakai. 1997. The ΦX174-type primosome promotes replisome assembly at the site of recombination in bacteriophage Mu transposition. EMBO J. 16:6886-6895.