Photo of Ralph Scully,  MBBS, PhD

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 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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  • Menghi F, Inaki K, Woo X, Kumar PA, Grzeda KR, Malhotra A, Yadav V, Kim H, Marquez EJ, Ucar D, Shreckengast PT, Wagner JP, MacIntyre G, Murthy Karuturi KR, Scully R, Keck J, Chuang JH, Liu ET. The tandem duplicator phenotype as a distinct genomic configuration in cancer. Proc Natl Acad Sci U S A 2016; 113:E2373-82. PubMed
  • Elia AE, 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; 60:280-93. PubMed
  • 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
  • Liu XS, 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. Nat Commun 2015; 6:8325. PubMed
  • Hu Y, Petit SA, Ficarro SB, Toomire KJ, Xie A, Lim E, Cao SA, Park E, Eck MJ, Scully R, Brown M, Marto JA, Livingston DM. PARP1-driven poly-ADP-ribosylation regulates BRCA1 function in homologous recombination-mediated DNA repair. 2014. 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, Guirouilh Barbat J, 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
  • Scully R, Xie A. Double strand break repair functions of histone H2AX. Mutat Res 2013; 750:5-14. 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
  • Pathania S, Nguyen J, Hill SJ, Scully R, Adelmant GO, Marto JA, Feunteun J, Livingston DM. BRCA1 is required for postreplication repair after UV-induced DNA damage. Mol Cell 2011. 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
  • 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
  • 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
  • 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,Hartlerode A,Stucki M,Odate S,Puget N,Kwok A,Nagaraju G,Yan C,Alt FW,Chen J,Jackson SP,Scully R. Distinct roles of chromatin-associated proteins MDC1 and 53BP1 in mammalian double-strand break repair. Mol Cell 2007; 28:1045-57. 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
  • 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
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