Brehon C Laurent, PhD
- ADJUNCT ASSOCIATE PROFESSOR | Oncological Sciences
AB, Bowdoin College
PhD, Massachusetts Institute of Technology
State University of New York Chancellor??s Research Award
Basil O'Connor Starter Scholar Research Award
Individual National Research Service Award
Chromosome dynamics during the processes of chromosome segregation, the maintenance of genome integrity, and gene transcription
Our laboratory studies how dynamic changes in chromatin structure regulate the fundamental cellular events of chromosome segregation, DNA damage repair, and gene transcription. In particular, we study the mechanisms by which RSC and Swi/Snf, two conserved ATP-utilizing chromatin-remodeling complexes, control these processes. Defects in the remodeling of chromatin can lead to cancers and severe genetic diseases, and human SWI/SNF counterpart proteins have been shown to function as powerful tumor suppressors. We use the simple eukaryote Saccharomyces cerevisiae as the model system and will extend these experiments in mammalian cells.
Studies in our laboratory established a key role for the RSC chromatin-remodeling activity in regulating chromatin folding during genomic transmission. We found that RSC's remodeling activity is required for the function of the centromere-kinetochore (Hsu et al. 2003), the region of the chromosome that is responsible for segregating sister chromatids to daughter cells during cell division. More recently,we've shown that RSC facilitates the loading of cohesin onto the arms of newly replicated sister chromatids (Huang et al. 2004; Figs. 1 and 2). Future experiments will test RSC's role in establishing and/or maintaining the cohesion and condensation of sister chromatids for proper partitioning.
The accurate and efficient repair of the ~104 DNA damage events per day for a mammalian cell are essential for survival; unrepaired DNA lesions disrupt chromosomal integrity and can result in cancers. Moreover, such lesions must be repaired in the context of chromatin. Recent experiments suggest novel roles for both RSC and Swi/Snf in processing DNA double-strand breaks (DSBs) (Chai et al. 2005; Fig. 3). Current efforts are directed towards defining how these ATP-dependent remodelers contribute to the chromatin dynamics required to maintain genome integrity. Translational experiments in mammalian cells will explore roles of the SWI/SNF orthologs in partitioning and repairing the genome during the cell cycle, providing insight into their roles in tumorigenesis.
In another study, we have uncovered a rapid, biphasic response mechanism that relies on the coordinated recruitment of Swi/Snf and histone acetyltransferase activities (Fig. 4). Future experiments will examine at the molecular level how the chromatin-modifying activities are regulated as well as how these phases communicate to properly regulate transcription.
Huang J, Liang B, Qiu J, Laurent BC. ATP-dependent chromatin-remodeling complexes in DNA double-strand break repair: remodeling, pairing, and (re)pairing. Cell Cycle 2005;(4): 1713-1715.
Wong LY, Recht J, Laurent BC. Chromatin remodeling and repair of DNA double-strand breaks. J. Mol. Histol. 2006;(37): 261-269.
Liang B, Qiu J, Ratnakumar K, Laurent BC. RSC functions as an early double-strand break sensor in the cell's response to DNA damage. Curr. Biol. 2007;(17): 1432-1437.
Du J, Nasir I, Benton BK, Kladde MP, Laurent BC. Sth1p, a Saccharomyces cerevisiae Snf2p/Swi2p homolog, is an essential ATPase in RSC and differs from Snf/Swi in its interactions with histones and chromatin-associated proteins. Genetics 1998 Nov; 150(3): 987-1005.
Sudarsanam P, Cao Y, Wu L, Laurent BC, Winston F. The nucleosome remodeling complex, Snf/Swi, is required for the maintenance of transcription in vivo and is partially redundant with the histone acetyltransferase, Gcn5. EMBO J 1999 Jun; 18(11): 3101-3106.