BBS Faculty Member - Ralph Scully

Ralph Scully

Department of Medicine


Beth Israel Deaconess Medical Center
Division of Hematology-Oncology/Cancer Research Institute
Center for Life Sciences, CLS 438
3 Blackfan Circle
Boston, MA 02115
Tel: 617-735-2041
Fax: 617-735-2222
Email: rscully@bidmc.harvard.edu



We study 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. Indeed, defects in HR, caused by germ line mutation of one of two major hereditary breast/ovarian cancer predisposition genes, BRCA1 and BRCA2, are significant contributors to cancer risk in the human population.

BRCA1 and BRCA2, together with interacting recombination proteins such as Rad51, mediate an error-free form of HR called “sister chromatid recombination” (SCR). Approximately twenty years ago, we proposed that
BRCA genes function as tumor suppressors by controlling SCR at sites of replication fork stalling in replicating cells. We adapted the Escherichia coli Tus/Ter replication fork barrier for use in mammalian cells, enabling us stall the mammalian replisome at a defined chromosomal locus, following transient expression of the Tus polypeptide. This new tool enables us to address fundamental questions regarding the biology of the mammalian stalled fork response, ranging from biochemical analyses to the molecular characterization of repair processes triggered by fork stalling. Our work has revealed that the “rules” of repair at stalled forks differs substantially from those governing repair of a conventional chromosomal double strand break. We found that BRCA1 and BRCA2 suppress error-prone replicative responses at stalled forks—a process potentially analogous to “break-induced replication” in yeast. This finding suggested a new mechanism, specific to the stalled fork, by which loss of BRCA genes may promote genomic instability and cancer. Our most recent work has revealed the mechanism underlying a novel tandem duplicator phenotype in BRCA1 mutant cancers, which we find is also triggered specifically by fork stalling. These lines of research have enabled us to begin to model complex chromosomal rearrangements arising from defective processing of the stalled fork.

Many human
BRCA variants are known to be either neutral or pathogenic. Others, termed BRCA “variants of uncertain significance” (VUS), are difficult to classify due to their scarcity in the human population. Since the cancer risk associated with VUS alleles is unknown, it is not clear what prophylactic interventions, if any, are appropriate for a woman who carries a BRCA VUS allele. Our underlying hypothesis is that the HR function of a given BRCA variant can be used to predict its status as a neutral or pathogenic variant. We developed a method to rapidly analyze the HR functions of individual BRCA1 variants. In collaboration with a number of cancer genetics labs, we are using this assay in an attempt to predict cancer risk associated with individual BRCA1 VUS alleles.



Last Update: 3/13/2017



Publications

For a complete listing of publications click here.

 


 

Willis NA, Chandramouly G, Huang B, Kwok A, Follonier C, Deng C and Scully R. BRCA1 controls homologous recombination at Tus/Ter-stalled mammalian replication forks. Nature, 2014; 510:556-9. doi: 10.1038/nature13295. Epub 2014 Apr 28.

Liu X-S, Chandramouly G, Rass E, Guan Y, Wang G, Hobbs RM, Rajendran A, Xie A, Shah JV, Davis AJ, Scully R*, Lunardi A*, Pandolfi PP*. LRF maintains genome integrity by regulating the non-homologous end joining pathway of DNA repair.
Nature Communications, 2015 Oct 8;6:8325. doi: 10.1038/ncomms9325.
*joint corresponding authors

Elia AEH, Wang DC, Willis NA, Boardman AP, Hajdu I, Adeyemi RO, Lowry E, Gygi SP, Scully R, Elledge SJ. RFWD3-Dependent Ubiquitination of RPA Regulates Repair at Stalled Replication Forks.
Mol Cell. 2015 Oct 15;60(2):280-93. doi: 10.1016/j.molcel.2015.09.011.

Willis NA, Rass E and Scully R. Deciphering the Code of the Cancer Genome: Mechanisms of Chromosome Rearrangement.
Trends in Cancer, 2015 Dec 1;1(4):217-230.

Menghi F, Inaki K, Woo X-Y, Kumar PA, Grzeda KR, Malhotra A, Yadav V, Kim H, Marquez EJ, Ucar D, Shreckengast PT, Wagner JP, MacIntyre G, Karuturi RKM,
Scully R, Keck J, Chuang JH, Liu ET. The tandem duplicator phenotype as a distinct genomic configuration in cancer. Proc Natl Acad Sci (USA) 2016 Apr 26;113(17):E2373-82. doi: 10.1073/pnas.1520010113. Epub 2016 Apr 7.

Hartlerode AJ, Willis NA, Rajendran A, Manis JP, Scully R. Complex breakpoints and template switching associated with non-canonical termination of homologous recombination in mammalian cells.
PLoS Genetics 2016 Nov 10;12(11):e1006410. doi: 10.1371/journal.pgen.1006410.



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of Harvard College