BBS Faculty Member - Ralph Scully

Ralph Scully

Department of Medicine


Beth Israel Deaconess Med Ctr
Center for Life Sciences Room 438
3 Blackfan Circle
Boston, MA 02115
Tel: 617-735-2041
Fax: 617-735-2222
Email: rscully@bidmc.harvard.edu
Lab Members: 6 postdoctoral fellows



We are interested in the relationships between mammalian double strand break (DSB) repair, genomic instability and cancer. Two major pathways contribute to DSB repair: homologous recombination (HR) and non-homologous end joining (NHEJ). Each plays a key role in suppressing cancer and aging in mammals.

1. Functional analysis of BRCA1 and BRCA2:
The major hereditary breast/ovarian cancer predisposition genes, BRCA1 and BRCA2, have critical roles in HR. Circumstantial evidence suggests that BRCA1 and BRCA2, together with interacting recombination proteins such as Rad51, mediate an error-free form of HR called “sister chromatid recombination” (SCR). We developed a specific reporter of SCR and are using it to analyze the relationships between BRCA1 and BRCA2 dysfunction, defective SCR and genomic instability. We are developing mouse models that will enable the direct quantitation of SCR in vivo, during normal development and in disease states. Our second major goal in this area is to discover new therapies that selectively target HR-defective BRCA mutant breast/ovarian cancers. To this end, we are conducting genome-wide screens for new mammalian DSB repair genes and chemical library screens to identify small molecules that selectively target HR-defective cancers.

2. Real time imaging of the mammalian DSB response: To better understand how the mammalian DSB response is orchestrated in space and time, we have developed a multi-photon laser (MPL) system for targeting DSBs to defined, subfemtoliter volumes within the mammalian nucleus. The MPL system combines spatially defined, titratable levels of DNA damage with real time imaging of fluorescent DSB response proteins as they accumulate and disperse from the site of MPL-induced breakage. This provides accurate quantitation of DSB response kinetics and has enabled us to mathematically model elements of the mammalian DSB response. We are currently studying the kinetics of the DSB response during the first few minutes following break induction. This has also entailed developing tools to study the chromatin response to chromosome breaks in real time.

3. The replication-recombination interface: A major trigger to genomic instability is thought to be the stalling of a DNA polymerase complex at sites of abnormal DNA structure. Paradoxically, there are few tools available to study in molecular detail how mammalian DNA polymerase stalling activates HR or triggers genomic instability. We have recently developed a novel set of molecular tools to trigger DNA polymerase stalling and HR at a specific genomic locus. We are using this new technology to study mechanisms underlying the replication-recombination interface in mammalian cells.



Last Update: 8/22/2013



Publications

For a complete listing of publications click here.

 


 

Xie A, Hartlerode A, Stucki M, Odate S, Puget N, Kwok A, Nagaraju G, Yan C, Alt FW, Chen J, Jackson SP and Scully R. Distinct Roles of Chromatin-Associated Proteins MDC1 and 53BP1 in Mammalian Double-Strand Break Repair. Mol Cell 2007; 28: 1045-1057.

Xie A, Kwok A and Scully R. Role of mammalian Mre11 in classical and alternative non-homologous end joining.
Nature Struct Mol Biol 2009; 16: 814-818.

Hartlerode A, Odate S, Shim I, Brown J, and Scully R. Cell cycle-dependent induction of homologous recombination by a tightly regulated I-SceI fusion protein.
PLoS One. 2011 Mar 9;6(3):e16501.



© 2013 by the President and Fellows of Harvard College