Our Science – Wu Website

Carl Wu, Ph.D.

Laboratory of Biochemistry and Molecular Biology Head, Chromosome Structure and Gene Regulation Section Laboratory Chief National Cancer Institute Building 37, Room 6068 Bethesda, MD 20892 Phone:   301-496-3029 Fax:   301-435-3697 E-Mail:   carlwu@helix.nih.gov

Biography

Dr. Wu received his Ph.D. (1979) under Sarah Elgin at Harvard University, where he began studies of chromatin organization at specific genes. As a Junior Fellow at Harvard under Nobel laureate Wally Gilbert, he provided the first evidence that chromatin is reshaped at cellular gene promoters. After moving to the NCI in 1982, Dr. Wu began investigating the biochemical mechanism of chromatin remodeling. In 1994, his group reported the discovery of an ATP-dependent chromatin remodeling activity in cell-free extracts, and in the following year, purification and characterization of the responsible enzyme, named NURF. This work has been noted by Nature as a milestone in the field of gene expression over the past 50 years. Dr. Wu has been recognized by a number of prize awards and by election to the American Academy of Arts and Sciences, the Academia Sinica, and the National Academy of Sciences.

Research

Our group is interested in how nucleosomes, the fundamental units of chromatin organization, are dynamically reshaped by ATP-driven, multi-protein chromatin 'remodeling' enzymes. At the heart of our approach is the development of biochemical assays to identify key components and elucidate mechanisms of action; these are supplemented with other tools of modern biology (genetics, biophysics, cell biology, genomics and proteomics).

We are continuing long-term studies of NURF, a prototypical ISWI complex that catalyzes histone octamer sliding, a mechanism that moves nucleosomes to allow gene activation or repression without loss of histone octamer integrity. Genetic studies in Drosophila indicate that NURF plays a critical role in both positive and negative regulation of several hundred genes, including those involved in the response to environmental stress and to cytokine and steroid hormone signals, and genes specifying cell fates in development. NURF is recruited to chromatin by gene-specific transcription factors as well as trimethylated lysine 4 of histone H3. Current studies of mouse knockouts of the largest NURF subunit, BPTF have uncovered its requirement for early embryonic development.

Our studies of the yeast SWR1 complex led to the startling finding that SWR1 specifically catalyzes the replacement of conventional histone H2A for histone H2AZ, a histone variant incorporated around gene promoters. Thus, chromatin remodeling involves not only histone octamer sliding, but also the eviction of a canonical histone and its replacement with a histone variant. We are continuing to investigate the molecular mechanisms of histone H2AZ replacement by analysis of mutant enzymes lacking one or several SWR1 components, and by developing biochemical assays to elucidate the process of histone H2A-H2B eviction, H2AZ-H2B replacement, and promoter targeting.

Most recently, studies of CenH3, the centromere specific H3 histone variant of budding yeast revealed an interacting nonhistone protein Scm3, that forms a 1:1:1 complex with CenH3 and histone H4. Scm3 may replace conventional histones H2A-H2B at budding yeast point centromeres, and is the first example of a nonhistone protein that associates stoichiometrically with histones in a surprisingly deviant form of the canonical histone octamer. Current studies aim to investigate the biology of Scm3 and elucidate how the Scm3-CenH3-H4 complex associates with inner kinetochore proteins and centromeric DNA to nucleate assembly and function of the chromosome kinetochore.

This page was last updated on 6/12/2008.