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

Photo of Ralph Scully, MBBS, PhD

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


rscully@bidmc.harvard.edu

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Ralph Scully, MBBS, PhD

Beth Israel Deaconess Medical Center

EDUCATIONAL TITLES

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

DF/HCC PROGRAM AFFILIATION

Research Abstract

We study the relationships between homologous recombination (HR), genomic instability and hereditary breast/ovarian cancer predisposition. Our work has revealed new functions for the major breast/ovarian cancer susceptibility genes, BRCA1 and BRCA2, in regulating HR at sites of stalled replication. In recent work, we have elucidated the mechanisms underlying certain characteristic “rearrangement signatures” in BRCA1-linked cancers. The elucidation of stalled fork repair pathways that are controlled by BRCA1 and BRCA2 may help to identify promising new biomarkers and new therapeutic approaches in BRCA-linked breast and ovarian cancer.

Publications from Harvard Catalyst Profiles

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  • Panday A, Willis NA, Elango R, Menghi F, Duffey EE, Liu ET, Scully R. FANCM regulates repair pathway choice at stalled replication forks. Mol Cell 2021. PubMed
  • Willis NA, Scully R. Measurement of Homologous Recombination at Stalled Mammalian Replication Forks. Methods Mol Biol 2021; 2153:329-353. PubMed
  • Luo ML, Zheng F, Chen W, Liang ZM, Chandramouly G, Tan J, Willis NA, Chen CH, de Oliveira Taveira M, Zhou XZ, Lu KP, Scully R, Wulf GM, Hu H. Inactivation of the prolyl isomerase Pin1 sensitizes BRCA1-proficient breast cancer to PARP inhibition. Cancer Res 2020. PubMed
  • Monteiro AN, Bouwman P, Kousholt AN, Eccles DM, Millot GA, Masson JY, Schmidt MK, Sharan SK, Scully R, Wiesmüller L, Couch F, Vreeswijk MPG. Variants of uncertain clinical significance in hereditary breast and ovarian cancer genes: best practices in functional analysis for clinical annotation. J Med Genet 2020. PubMed
  • Scully R, Panday A, Elango R, Willis NA. DNA double-strand break repair-pathway choice in somatic mammalian cells. Nat Rev Mol Cell Biol 2019. PubMed
  • Menghi F, Barthel FP, Yadav V, Tang M, Ji B, Tang Z, Carter GW, Ruan Y, Scully R, Verhaak RGW, Jonkers J, Liu ET. The Tandem Duplicator Phenotype Is a Prevalent Genome-Wide Cancer Configuration Driven by Distinct Gene Mutations. Cancer Cell 2018; 34:197-210.e5. PubMed
  • Willis NA, Panday A, Duffey EE, Scully R. Rad51 recruitment and exclusion of non-homologous end joining during homologous recombination at a Tus/Ter mammalian replication fork barrier. PLoS Genet. 2018; 14:e1007486. PubMed
  • Willis NA, Frock RL, Menghi F, Duffey EE, Panday A, Camacho V, Hasty EP, Liu ET, Alt FW, Scully R. Mechanism of tandem duplication formation in BRCA1-mutant cells. Nature 2017; 551:590-595. PubMed
  • Nath S, Somyajit K, Mishra A, Scully R, Nagaraju G. FANCJ helicase controls the balance between short- and long-tract gene conversions between sister chromatids. Nucleic Acids Res 2017; 45:8886-8900. PubMed
  • Hwang Y, Futran M, Hidalgo D, Pop R, Iyer DR, Scully R, Rhind N, Socolovsky M. Global increase in replication fork speed during a p57(KIP2)-regulated erythroid cell fate switch. Sci Adv 2017; 3:e1700298. PubMed
  • Smith EA, Gole B, Willis NA, Soria R, Starnes LM, Krumpelbeck EF, Jegga AG, Ali AM, Guo H, Meetei AR, Andreassen PR, Kappes F, Vinnedge LM, Daniel JA, Scully R, Wiesmüller L, Wells SI. DEK is required for homologous recombination repair of DNA breaks. Sci Rep 2017; 7:44662. PubMed
  • 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 Genet. 2016; 12:e1006410. PubMed
  • Guirouilh-Barbat J, Gelot C, Xie A, Dardillac E, Scully R, Lopez BS. 53BP1 Protects against CtIP-Dependent Capture of Ectopic Chromosomal Sequences at the Junction of Distant Double-Strand Breaks. PLoS Genet. 2016; 12:e1006230. PubMed
  • Willis NA, Scully R. DNA Polymerase θ: Duct Tape and Zip Ties for a Fragile Genome. Mol Cell 2016; 63:542-4. PubMed
  • Juvekar A, Hu H, Yadegarynia S, Lyssiotis CA, Ullas S, Lien EC, Bellinger G, Son J, Hok RC, Seth P, Daly MB, Kim B, Scully R, Asara JM, Cantley LC, Wulf GM. Phosphoinositide 3-kinase inhibitors induce DNA damage through nucleoside depletion. Proc Natl Acad Sci U S A 2016; 113:E4338-47. PubMed
  • Willis NA, Scully R. Spatial separation of replisome arrest sites influences homologous recombination quality at a Tus/Ter-mediated replication fork barrier. Cell Cycle 2016. PubMed
  • 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
  • Willis NA, Rass E, Scully R. Deciphering the Code of the Cancer Genome: Mechanisms of Chromosome Rearrangement. Trends Cancer 2015; 1:217-230. 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
  • 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,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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DF/HCC members that share similar concepts* with Ralph Scully, MBBS, PhD but have yet to coauthor a publication with this researcher.

* Concepts are MeSH terms, automatically derived from member publications

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