Research Summary

Physical and Genetic Interaction Networks Governing Pathway Deregulation in Cancer

Cancers have been associated with diverse sets of genomic alterations, many of which have unidentified roles in tumorigenesis. Notably, different genetic drivers of a trait often aggregate, rather than randomly located, in the molecular networks such as those that underlie protein complexes or signaling pathways, emphasizing the importance of network-based approaches in cancer research. We investigate protein-protein and genetic interactions, using the large-scale proteomics and genomics, to dissect functions of protein complexes and biological pathways during cellular proliferation and/or tumorigenesis as they are formed and turned on. Indeed, our analysis identifies novel PIK3CA-interacting proteins which repress PI3K-AKT signaling, and UBE2N as a BRCA1 interactor predictive of clinical response to inhibition of PARP in the context of the I-SPY 2 clinical trial. Thus, cancer protein interaction landscapes provide a framework to recognize oncogenic drivers and drug vulnerabilities, for which new and effective therapeutic strategies could be developed.

Functional Interactome of DNA Damage Response-Deficient Breast Cancer

The DNA damage response (DDR) requires the interaction of proteins involved in DNA repair, and that the coordinated regulation of these interactions is fundamental to maintain genome stability. To define functional DDR interactome, we identified 240 proteins that physically interact with 10 breast cancer susceptible DNA repair proteins (BRCA1, BRCA2, BRIP1, CHEK2, PALB2, RAD51C, RAD51D, MLH1, MSH2, XPC), and assessed the role of these interacting proteins in DDR by analyzing cellular response to DDR-targeting drugs (cisplatin and olaparib) upon knocking these genes out by CRISPR/Cas9. These efforts uncovered multiple novel “BRCAness” genes to which current BRCA-targeted therapy could be applied. Furthermore, this approach identified a novel protein (Spinophilin) which interacts with BRCA1. Both knockdown and overexpression of Spinophilin led to significant impairment in DNA double-strand break repair by homologous recombination and single-strand annealing pathways, establishing that this protein has a defined role in DNA repair. Phospho-proteomic analysis indicates that Spinophilin dephosphorylates and thus modulates BRCA1 functions via direct interaction. Importantly, Spinophilin is frequently amplified in ~8% (87 out of 1093) of sequenced breast cancer patient tumors (TCGA Study), which is higher than the alteration frequency of BRCA1 (3%) and BRCA2 (4%). Our finding suggests that Spinophilin-amplified tumors may arise due to abnormal regulation of DDR.

Rational Repurposing of Kinase Inhibitors for SARS-CoV-2 Combination Therapy

The development of therapeutic strategies against the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is an urgent global research priority. Identifying host targets of SARS-CoV-2 offers the potential to develop efficient therapies with a fast development timeline by avoiding viral escape mechanisms and utilizing repurposed FDA-approved drugs. We recently identified 332 host factors that interact with SARS-CoV-2, including 66 that are targeted by 109 FDA-approved drugs, investigational new drugs (INDs), and preclinical compounds. Among these, inhibitors of mRNA translation and predicted regulators of the Sigma1 and Sigma2 receptors demonstrated antiviral activity in vitro. To obtain additional potential drug targets, we utilized the orthogonal approach of global phosphorylation proteomic profiling upon SARS-CoV-2 infection in Vero E6 cells to gain a snapshot of signaling pathways that are rewired during virus infection. Profiling of differentially regulated kinase activities and pathways revealed 87 kinase inhibitors, with inhibitors of p38, CK2, CDKs, AXL, and PIKFYVE kinases all showing in vitro antiviral activity. We will further expand on the portfolio of pharmacological interventions and drug repurposing by analyzing the proteome-wide impact of SARS-CoV-2 on protein abundance and phosphorylation over a clinically relevant time-course of infection in human cells.

Education

Korea Advanced Institute of Science and Technology (KAIST), Korea, B.Sc., 02/1992, Biology (Cum laude)
Seoul National University, Korea, M.S,. 02/1995, Molecular Biology
Seoul National University, Korea, Ph.D., 08/2000, Molecular Biology
Seoul National University, Korea, Postdoc, 02/2001, Molecular Biology
Harvard Medical School, MA, USA, Postdoc, 12/2009, Biochemistry/Proteomics

Honors & Awards

  • 1992
    Cum laude, Korea Advanced Institute of Science and Technology, Korea
  • 1995 – 1996
    Pre-doctoral Fellowship for Future Researchers, Korea Research Foundation
  • 2004
    BCMP Discovery of the Year Award, Harvard Medical School
  • 2005 – 2007
    Charles A. King Trust Post-Doctoral Fellowship, the Medical Foundation, MA
  • 2016 – 2017
    Breast Cancer Research Fund (BCRF) Award, Helen Diller Family Comprehensive Cancer Center, UCSF
  • 2016 – 2017
    Program for Breakthrough Biomedical Research (PBBR) Award, UCSF

Selected Publications

  1. Chen H, Diolaiti ME, O'Leary PC, Rojc A, Krogan NJ, Kim M, Ashworth A. A whole genome CRISPR screen identifies AHR loss as a mechanism of PARP7 inhibitor resistance. Mol Cancer Ther. 2022 Apr 19.  View on PubMed
  2. Kim M, Park J, Bouhaddou M, Kim K, Rojc A, Modak M, Soucheray M, McGregor MJ, O'Leary P, Wolf D, Stevenson E, Foo TK, Mitchell D, Herrington KA, Muñoz DP, Tutuncuoglu B, Chen KH, Zheng F, Kreisberg JF, Diolaiti ME, Gordan JD, Coppé JP, Swaney DL, Xia B, van 't Veer L, Ashworth A, Ideker T, Krogan NJ. A protein interaction landscape of breast cancer. Science. 2021 Oct; 374(6563):eabf3066.  View on PubMed
  3. Swaney DL, Ramms DJ, Wang Z, Park J, Goto Y, Soucheray M, Bhola N, Kim K, Zheng F, Zeng Y, McGregor M, Herrington KA, O'Keefe R, Jin N, VanLandingham NK, Foussard H, Von Dollen J, Bouhaddou M, Jimenez-Morales D, Obernier K, Kreisberg JF, Kim M, Johnson DE, Jura N, Grandis JR, Gutkind JS, Ideker T, Krogan NJ. A protein network map of head and neck cancer reveals PIK3CA mutant drug sensitivity. Science. 2021 Oct; 374(6563):eabf2911.  View on PubMed
  4. Zheng F, Kelly MR, Ramms DJ, Heintschel ML, Tao K, Tutuncuoglu B, Lee JJ, Ono K, Foussard H, Chen M, Herrington KA, Silva E, Liu SN, Chen J, Churas C, Wilson N, Kratz A, Pillich RT, Patel DN, Park J, Kuenzi B, Yu MK, Licon K, Pratt D, Kreisberg JF, Kim M, Swaney DL, Nan X, Fraley SI, Gutkind JS, Krogan NJ, Ideker T. Interpretation of cancer mutations using a multiscale map of protein systems. Science. 2021 Oct; 374(6563):eabf3067.  View on PubMed
  5. Bouhaddou M, Memon D, Meyer B, White KM, Rezelj VV, Correa Marrero M, Polacco BJ, Melnyk JE, Ulferts S, Kaake RM, Batra J, Richards AL, Stevenson E, Gordon DE, Rojc A, Obernier K, Fabius JM, Soucheray M, Miorin L, Moreno E, Koh C, Tran QD, Hardy A, Robinot R, Vallet T, Nilsson-Payant BE, Hernandez-Armenta C, Dunham A, Weigang S, Knerr J, Modak M, Quintero D, Zhou Y, Dugourd A, Valdeolivas A, Patil T, Li Q, Hüttenhain R, Cakir M, Muralidharan M, Kim M, Jang G, Tutuncuoglu B, Hiatt J, Guo JZ, Xu J, Bouhaddou S, Mathy CJP, Gaulton A, Manners EJ, Félix E, Shi Y, Goff M, Lim JK, McBride T, O'Neal MC, Cai Y, Chang JCJ, Broadhurst DJ, Klippsten S, De Wit E, Leach AR, Kortemme T, Shoichet B, Ott M, Saez-Rodriguez J, tenOever BR, Mullins RD, Fischer ER, Kochs G, Grosse R, García-Sastre A, Vignuzzi M, Johnson JR, Shokat KM, Swaney DL, Beltrao P, Krogan NJ. The Global Phosphorylation Landscape of SARS-CoV-2 Infection. Cell. 2020 08 06; 182(3):685-712.e19.  View on PubMed
  6. Gordon DE, Jang GM, Bouhaddou M, Xu J, Obernier K, White KM, O'Meara MJ, Rezelj VV, Guo JZ, Swaney DL, Tummino TA, Hüttenhain R, Kaake RM, Richards AL, Tutuncuoglu B, Foussard H, Batra J, Haas K, Modak M, Kim M, Haas P, Polacco BJ, Braberg H, Fabius JM, Eckhardt M, Soucheray M, Bennett MJ, Cakir M, McGregor MJ, Li Q, Meyer B, Roesch F, Vallet T, Mac Kain A, Miorin L, Moreno E, Naing ZZC, Zhou Y, Peng S, Shi Y, Zhang Z, Shen W, Kirby IT, Melnyk JE, Chorba JS, Lou K, Dai SA, Barrio-Hernandez I, Memon D, Hernandez-Armenta C, Lyu J, Mathy CJP, Perica T, Pilla KB, Ganesan SJ, Saltzberg DJ, Rakesh R, Liu X, Rosenthal SB, Calviello L, Venkataramanan S, Liboy-Lugo J, Lin Y, Huang XP, Liu Y, Wankowicz SA, Bohn M, Safari M, Ugur FS, Koh C, Savar NS, Tran QD, Shengjuler D, Fletcher SJ, O'Neal MC, Cai Y, Chang JCJ, Broadhurst DJ, Klippsten S, Sharp PP, Wenzell NA, Kuzuoglu-Ozturk D, Wang HY, Trenker R, Young JM, Cavero DA, Hiatt J, Roth TL, Rathore U, Subramanian A, Noack J, Hubert M, Stroud RM, Frankel AD, Rosenberg OS, Verba KA, Agard DA, Ott M, Emerman M, Jura N, von Zastrow M, Verdin E, Ashworth A, Schwartz O, d'Enfert C, Mukherjee S, Jacobson M, Malik HS, Fujimori DG, Ideker T, Craik CS, Floor SN, Fraser JS, Gross JD, Sali A, Roth BL, Ruggero D, Taunton J, Kortemme T, Beltrao P, Vignuzzi M, García-Sastre A, Shokat KM, Shoichet BK, Krogan NJ. A SARS-CoV-2 protein interaction map reveals targets for drug repurposing. Nature. 2020 07; 583(7816):459-468.  View on PubMed
  7. Bouhaddou M, Eckhardt M, Chi Naing ZZ, Kim M, Ideker T, Krogan NJ. Mapping the protein-protein and genetic interactions of cancer to guide precision medicine. Curr Opin Genet Dev. 2019 02; 54:110-117.  View on PubMed
  8. Kim K, Heo DH, Kim I, Suh JY, Kim M. Exosome Cofactors Connect Transcription Termination to RNA Processing by Guiding Terminated Transcripts to the Appropriate Exonuclease within the Nuclear Exosome. J Biol Chem. 2016 Jun 17; 291(25):13229-42.  View on PubMed
  9. Park J, Kang M, Kim M. Unraveling the mechanistic features of RNA polymerase II termination by the 5'-3' exoribonuclease Rat1. Nucleic Acids Res. 2015 Mar 11; 43(5):2625-37.  View on PubMed
  10. Heo DH, Yoo I, Kong J, Lidschreiber M, Mayer A, Choi BY, Hahn Y, Cramer P, Buratowski S, Kim M. The RNA polymerase II C-terminal domain-interacting domain of yeast Nrd1 contributes to the choice of termination pathway and couples to RNA processing by the nuclear exosome. J Biol Chem. 2013 Dec 20; 288(51):36676-90.  View on PubMed
  11. Lunde BM, Reichow SL, Kim M, Suh H, Leeper TC, Yang F, Mutschler H, Buratowski S, Meinhart A, Varani G. Cooperative interaction of transcription termination factors with the RNA polymerase II C-terminal domain. Nat Struct Mol Biol. 2010 Oct; 17(10):1195-201.  View on PubMed
  12. Kim M, Suh H, Cho EJ, Buratowski S. Phosphorylation of the yeast Rpb1 C-terminal domain at serines 2, 5, and 7. J Biol Chem. 2009 Sep 25; 284(39):26421-6.  View on PubMed
  13. Vasiljeva L, Kim M, Mutschler H, Buratowski S, Meinhart A. The Nrd1-Nab3-Sen1 termination complex interacts with the Ser5-phosphorylated RNA polymerase II C-terminal domain. Nat Struct Mol Biol. 2008 Aug; 15(8):795-804.  View on PubMed
  14. Vasiljeva L, Kim M, Terzi N, Soares LM, Buratowski S. Transcription termination and RNA degradation contribute to silencing of RNA polymerase II transcription within heterochromatin. Mol Cell. 2008 Feb 15; 29(3):313-23.  View on PubMed
  15. Dion MF, Kaplan T, Kim M, Buratowski S, Friedman N, Rando OJ. Dynamics of replication-independent histone turnover in budding yeast. Science. 2007 Mar 09; 315(5817):1405-8.  View on PubMed
  16. Kim M, Vasiljeva L, Rando OJ, Zhelkovsky A, Moore C, Buratowski S. Distinct pathways for snoRNA and mRNA termination. Mol Cell. 2006 Dec 08; 24(5):723-734.  View on PubMed
  17. Liu CL, Kaplan T, Kim M, Buratowski S, Schreiber SL, Friedman N, Rando OJ. Single-nucleosome mapping of histone modifications in S. cerevisiae. PLoS Biol. 2005 Oct; 3(10):e328.  View on PubMed
  18. Kim M, Krogan NJ, Vasiljeva L, Rando OJ, Nedea E, Greenblatt JF, Buratowski S. The yeast Rat1 exonuclease promotes transcription termination by RNA polymerase II. Nature. 2004 Nov 25; 432(7016):517-22.  View on PubMed
  19. Kim M, Ahn SH, Krogan NJ, Greenblatt JF, Buratowski S. Transitions in RNA polymerase II elongation complexes at the 3' ends of genes. EMBO J. 2004 Jan 28; 23(2):354-64.  View on PubMed
  20. Ahn SH, Kim M, Buratowski S. Phosphorylation of serine 2 within the RNA polymerase II C-terminal domain couples transcription and 3' end processing. Mol Cell. 2004 Jan 16; 13(1):67-76.  View on PubMed

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