Ralph Scully, MBBS, PhD

Beth Israel Deaconess Medical Center

Beth Israel Deaconess Medical Center
Phone: (617) 735-2041
Fax: (617) 735-2222


rscully@bidmc.harvard.edu

Ralph Scully, MBBS, PhD

Beth Israel Deaconess Medical Center

EDUCATIONAL TITLES

  • Associate Professor, Medicine, Harvard Medical School
  • Associate Professor, Medicine, Beth Israel Deaconess Medical Center

DF/HCC PROGRAM AFFILIATION

Research Abstract

We are interested in the hereditary breast/ovarian cancer predisposition syndromes, with particular emphasis upon the basic biology of BRCA1 and BRCA2. Each gene product interacts with the Rad51 recombinase, a protein with a central role in homologous recombination. Consistent with this, dysfunction in either BRCA1 or BRCA2 produces chromosome breakage and profound genomic instability. Circumstantial evidence suggests that the BRCA1/BRCA2/Rad51 complex acts particulary during the S and G2 phases of the cell cycle, suggesting a potential role in sister chromatid recombination. We are using biochemical and genetic approaches in an effort to determine precisely how BRCA1 and BRCA2 regulate Rad51 functions and to understand the relationship between recombination and breast/ovarian cancer. As part of this work, we have devised novel assays for quantifying recombination between sister chromatids, and are currently applying them in the study of BRCA1 and BRCA2 function.

Publications

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  • Liu P, Gan W, Guo C, Xie A, Gao D, Guo J, Zhang J, Willis N, Su A, Asara JM, Scully R, Wei W. Akt-mediated phosphorylation of XLF impairs non-homologous end-joining DNA repair. Mol Cell 2015; 57:648-61. PubMed
  • Willis NA, Chandramouly G, Huang B, Kwok A, Follonier C, Deng C, Scully R. BRCA1 controls homologous recombination at Tus/Ter-stalled mammalian replication forks. Nature 2014. PubMed
  • Beck C, Boehler C, Barbat JG, Bonnet ME, Illuzzi G, Ronde P, Gauthier LR, Magroun N, Rajendran A, Lopez BS, Scully R, Boussin FD, Schreiber V, Dantzer F. PARP3 affects the relative contribution of homologous recombination and nonhomologous end-joining pathways. Nucleic Acids Res 2014. PubMed
  • Liu Y, Marks K, Cowley GS, Carretero J, Liu Q, Nieland TJ, Xu C, Cohoon TJ, Gao P, Zhang Y, Chen Z, Altabef AB, Tchaicha JH, Wang X, Choe S, Driggers EM, Zhang J, Bailey ST, Sharpless NE, Hayes DN, Patel NM, Janne PA, Bardeesy N, Engelman JA, Manning BD, Shaw RJ, Asara JM, Scully R, Kimmelman A, Byers LA, Gibbons DL, Wistuba II, Heymach JV, Kwiatkowski DJ, Kim WY, Kung AL, Gray NS, Root DE, Cantley LC, Wong KK. Metabolic and functional genomic studies identify deoxythymidylate kinase as a target in LKB1-mutant lung cancer. 2013; 3:870-9. PubMed
  • Chandramouly G, Kwok A, Huang B, Willis NA, Xie A, Scully R. BRCA1 and CtIP suppress long-tract gene conversion between sister chromatids. Nat Commun 2013; 4:2404. PubMed
  • Juvekar A, Burga LN, Hu H, Lunsford EP, Ibrahim YH, Balmañà J, Rajendran A, Papa A, Spencer K, Lyssiotis CA, Nardella C, Pandolfi PP, Baselga J, Scully R, Asara JM, Cantley LC, Wulf GM. Combining a PI3K Inhibitor with a PARP Inhibitor Provides an Effective Therapy for BRCA1-Related Breast Cancer. 2012; 2:1048-63. PubMed
  • Nguyen CL, Possemato R, Bauerlein EL, Xie A, Scully R, Hahn WC. Nek4 regulates entry into replicative senescence and the response to DNA damage in human fibroblasts. Mol Cell Biol 2012; 32:3963-77. PubMed
  • Hartlerode AJ, Guan Y, Rajendran A, Ura K, Schotta G, Xie A, Shah JV, Scully R. Impact of histone H4 lysine 20 methylation on 53BP1 responses to chromosomal double strand breaks. PLoS ONE 2012; 7:e49211. PubMed
  • Hu Y, Scully R, Sobhian B, Xie A, Shestakova E, Livingston DM. RAP80-directed tuning of BRCA1 homologous recombination function at ionizing radiation-induced nuclear foci. Genes Dev 2011; 25:685-700. PubMed
  • Hartlerode A, Odate S, Shim I, Brown J, Scully R. Cell Cycle-Dependent Induction of Homologous Recombination by a Tightly Regulated I-SceI Fusion Protein. PLoS ONE 2011; 6:e16501. PubMed
  • Scully R. The spindle-assembly checkpoint, aneuploidy, and gastrointestinal cancer. N Engl J Med 2010; 363:2665-6. PubMed
  • Xie A, Odate S, Chandramouly G, Scully R. H2AX post-translational modifications in the ionizing radiation response and homologous recombination. Cell Cycle 2010; 9:3602-10. PubMed
  • Scully R. A histone code for DNA repair. Nat Rev Mol Cell Biol 2010; 11:164. PubMed
  • Hartlerode AJ, Scully R. Mechanisms of double-strand break repair in somatic mammalian cells. Biochem J 2009; 423:157-68. PubMed
  • Xie A, Kwok A, Scully R. Role of mammalian Mre11 in classical and alternative nonhomologous end joining. Nat Struct Mol Biol 2009; 16:814-8. PubMed
  • Nagaraju G,Hartlerode A,Kwok A,Chandramouly G,Scully R. XRCC2 and XRCC3 regulate the balance between short- and long-tract gene conversion between sister chromatids. Mol Cell Biol 2009; 29:4283-94. PubMed
  • Oberdoerffer P,Michan S,McVay M,Mostoslavsky R,Vann J,Park SK,Hartlerode A,Stegmuller J,Hafner A,Loerch P,Wright SM,Mills KD,Bonni A,Yankner BA,Scully R,Prolla TA,Alt FW,Sinclair DA. SIRT1 redistribution on chromatin promotes genomic stability but alters gene expression during aging. Cell 2008; 135:907-18. PubMed
  • Lipshultz SE, Alvarez JA, Scully RE. Anthracycline associated cardiotoxicity in survivors of childhood cancer. Heart 2008; 94:525-33. PubMed
  • Xie A, Scully R. Hijacking the DNA damage response to enhance viral replication: gamma-herpesvirus 68 orf36 phosphorylates histone H2AX. Mol Cell 2007; 27:178-9. PubMed
  • Nagaraju G, Scully R. Minding the gap: The underground functions of BRCA1 and BRCA2 at stalled replication forks. DNA Repair (Amst) 2007; 6:1018-31. PubMed
  • Barry E, Alvarez JA, Scully RE, Miller TL, Lipshultz SE. Anthracycline-induced cardiotoxicity: course, pathophysiology, prevention and management. Expert Opin Pharmacother 2007; 8:1039-58. PubMed
  • Scully R, Xie A. In my end is my beginning: control of end resection and DSBR pathway 'choice' by cyclin-dependent kinases. Oncogene 2005; 24:2871-6. PubMed
  • Puget N, Knowlton M, Scully R. Molecular analysis of sister chromatid recombination in mammalian cells. DNA Repair (Amst) 2004; 4:149-61. PubMed
  • Xie A, Puget N, Shim I, Odate S, Jarzyna I, Bassing CH, Alt FW, Scully R. Control of sister chromatid recombination by histone H2AX. Mol Cell 2004; 16:1017-25. PubMed
  • Scully R, Xie A. BRCA1 and BRCA2 in breast cancer predisposition and recombination control. J Mammary Gland Biol Neoplasia 2004; 9:237-46. PubMed
  • Scully R, Xie A, Nagaraju G. Molecular functions of BRCA1 in the DNA damage response. Cancer Biol Ther 2004; 3:521-7. PubMed
  • Avni D, Yang H, Martelli F, Hofmann F, ElShamy WM, Ganesan S, Scully R, Livingston DM. Active localization of the retinoblastoma protein in chromatin and its response to S phase DNA damage. Mol Cell 2003; 12:735-46. PubMed
  • Scully R, Puget N. Hereditary breast and ovarian cancer genes. Methods Mol Biol 2003; 222:41-57. PubMed
  • Eichhorn JH, Young RH, Clement PB, Scully RE. Mesodermal (mlerian) adenosarcoma of the ovary: a clinicopathologic analysis of 40 cases and a review of the literature. Am J Surg Pathol 2002; 26:1243-58. PubMed
  • Bassing CH, Chua KF, Sekiguchi J, Suh H, Whitlow SR, Fleming JC, Monroe BC, Ciccone DN, Yan C, Vlasakova K, Livingston DM, Ferguson DO, Scully R, Alt FW. Increased ionizing radiation sensitivity and genomic instability in the absence of histone H2AX. Proc Natl Acad Sci U S A 2002; 99:8173-8. PubMed
  • Scully R, Puget N. BRCA1 and BRCA2 in hereditary breast cancer. Biochimie 2002; 84:95-102. PubMed
  • Scully R, Puget N, Vlasakova K. DNA polymerase stalling, sister chromatid recombination and the BRCA genes. Oncogene 2001; 19:6176-83. PubMed
  • Tibbetts RS, Cortez D, Brumbaugh KM, Scully R, Livingston D, Elledge SJ, Abraham RT. Functional interactions between BRCA1 and the checkpoint kinase ATR during genotoxic stress. Genes Dev 2000; 14:2989-3002. PubMed
  • Scully R, Livingston DM. In search of the tumour-suppressor functions of BRCA1 and BRCA2. Nature 2000; 408:429-32. PubMed
  • Eid JE, Kung AL, Scully R, Livingston DM. p300 interacts with the nuclear proto-oncoprotein SYT as part of the active control of cell adhesion. Cell 2000; 102:839-48. PubMed
  • Scully R, Ganesan S, Vlasakova K, Chen J, Socolovsky M, Livingston DM. Genetic analysis of BRCA1 function in a defined tumor cell line. Mol Cell 2000; 4:1093-9. PubMed
  • Oliva E, Young RH, Clement PB, Scully RE. Myxoid and fibrous endometrial stromal tumors of the uterus: a report of 10 cases. Int J Gynecol Pathol 1999; 18:310-9. PubMed
  • Chen JJ, Silver D, Cantor S, Livingston DM, Scully R. BRCA1, BRCA2, and Rad51 operate in a common DNA damage response pathway. Cancer Res 1999; 59:1752s-1756s. PubMed
  • Wilson CA, Ramos L, Villase. Localization of human BRCA1 and its loss in high-grade, non-inherited breast carcinomas. Nat Genet 1999; 21:236-40. PubMed
  • Chen J, Silver DP, Walpita D, Cantor SB, Gazdar AF, Tomlinson G, Couch FJ, Weber BL, Ashley T, Livingston DM, Scully R. Stable interaction between the products of the BRCA1 and BRCA2 tumor suppressor genes in mitotic and meiotic cells. Mol Cell 1998; 2:317-28. PubMed
  • Scully R, Chen J, Ochs RL, Keegan K, Hoekstra M, Feunteun J, Livingston DM. Dynamic changes of BRCA1 subnuclear location and phosphorylation state are initiated by DNA damage. Cell 1997; 90:425-35. PubMed
  • Scully R, Anderson SF, Chao DM, Wei W, Ye L, Young RA, Livingston DM, Parvin JD. BRCA1 is a component of the RNA polymerase II holoenzyme. Proc Natl Acad Sci U S A 1997; 94:5605-10. PubMed
  • Scully R, Chen J, Plug A, Xiao Y, Weaver D, Feunteun J, Ashley T, Livingston DM. Association of BRCA1 with Rad51 in mitotic and meiotic cells. Cell 1997; 88:265-75. PubMed
  • Yao TP, Ku G, Zhou N, Scully R, Livingston DM. The nuclear hormone receptor coactivator SRC-1 is a specific target of p300. Proc Natl Acad Sci U S A 1996; 93:10626-31. PubMed
  • Scully R, Ganesan S, Brown M, De Caprio JA, Cannistra SA, Feunteun J, Schnitt S, Livingston DM. Location of BRCA1 in human breast and ovarian cancer cells. Science 1996; 272:123-6. PubMed
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