- Laboratory
- DNA 손상 반응 연구실 (생화학/분자생물학/세포생물학)
- 연구실
- 자연대 1호관 430
- 연락처
- 062-530-3411
- 이메일
- microljh@jnu.ac.kr
세부내용
- Lab of DNA damage response
저희 연구실은 오가노이드를 모델 시스템으로 이용하여 특정 장기에서 genome instability와 protein homeostasis의 상실이 암과 신경퇴행성 질환의 발병과 진행과정에 미치는 영향을 생화학적, 분자생물학적, 그리고 세포 생물학적 방법으로 연구하고자 합니다. 또한 Genomics, Proteomics, 그리고 Transcriptomics를 이용한 다중오믹스적 연구방식을 이용하여 발견된 데이터를 분석함으로써 암과 신경퇴행성 질환의 새로운 병인을 찾고 앞으로 나아갈 연구 방향과 치료 방법의 개발을 위한 방향을 제시하고자 합니다. 장기 연구 주제는 ATM kinase가 다양한 스트레스 조건에서 Genome Stability를 유지하는 메커니즘을 더 깊게 이해하는 것입니다. DNA 손상이 복구되지 않거나 잘못 복구된 경우 종양 진행의 중요한 원인이 될 수 있기 때문에 genome instability는 일반적으로 암과 관련돼 연구됩니다. 저는 ATM protein을 효과적으로 정제하는 방법을 개발하고 (Lee and Paull, 2006, Methods Enzymol.) 다양한 Co-factor들과의 관계를 생화학적 실험 방법 ( Lee and Paull, 2004, 2005, Science)과 세포생물학적 연구 (Lee et al. 2018, Sci Signal. and Lee et al., 2021, Mol. Cell)로 증명해 왔습니다. 이로써, 저는 ATM이 Mre11-Rad50-Nbs1 (MRN) complex에 의해 DNA 이중가닥 손상 부위에서 활성화되고 많은 target substrate들을 phosphorylation 시킴으로써 세포 주기를 정지키고 DNA 복구 및 생존을 촉진시킨다는 것을 밝혀 DNA 이중 가닥 손상에의한 ATM activation pathway의 메케니즘을 정립하는데 큰 기여를 했습니다. 또한, 최근의 연구를 통해서, 저는 ATM 단백질이 결핍된 신경세포에서 산화 스트레스 (Oxidative Stress)가 DNA 단일가닥 손상의 축적을 유발하며 이로 인해 과활성화된 PARP 단백질에 의해서 단백질 응집 (Protein Aggregation)이 일어남을 증명했습니다 (Lee et al., 2021, Mol. Cell). 지금까지의 연구들을 바탕으로 독립적인 연구자로서, ATM kinase의 새로운 target substrate들을 Phospho-proteomics를 이용하여 발견하고 이들이 ATM protein에 의해 조절되는 메커니즘과 Genome Stability 유지와의 연관성을 생화학적 방법과 세포생물학적 방법을 이용하여 연구하고자 합니다. 또한, ATM gene의 mutation에 의해 발병하는 퇴행성 뇌질환의 일종인 Ataxia-Telangiectasia(A-T)병의 발병 원인과 진행과정을 Cerebellar Organoid를 이용하여 연구하고자 합니다.
- Education (학력)
Aug. 2000
─
Dec. 2005
Ph.D., Department of Molecular Genetics & Microbiology
University of Texas at Austin, Advisor: Tanya T. Paull, Ph.D.Mar. 1995
─
Feb. 1997
M.S., Biology, Inha University, Inchon, Korea
Advisor: Hong-Ui Han, Ph.D.
Mar. 1991
─
Feb. 1995
B.S., Biology, Inchon University, Inchon, Korea
- Research Experience (연구경력)
Mar. 2022
─
present
Associate Professor
Biological Science, Chonnam National Univ.Oct. 2019
─
Feb. 2022
Senior Scientist
Molecular Sciences, University of Texas at Austin
Sep. 2010
─
Sep. 2019
Research Specialist
Molecular Sciences, Howard Hughes Medical Institute
Sep. 2008
─
Aug. 2010
Research Associate
Molecular Sciences, Howard Hughes Medical Institute
Jan. 2006
─
Aug. 2008
Post-Doctoral Fellow
Molecular Genetics & Microbiology, University of Texas at Austin
- Publications (연구논문)
- 1. Lee JH, Paull TT., “Cellular functions of the protein kinase ATM and their relevance to human disease”, Nature Reviews Molecular Cell Biology, 22(12):796-814. (2021)
- 2. Lee JH, Ryu SW, Ender NA, Paull TT., “Poly-ADP-ribosylation drives loss of protein homeostasis in ATM and Mre11 deficiency”, Mol Cell., 81(7):1515-1533. (2021)
- 3. Somyajit K, Spies J, Coscia F, Kirik U, Rask MB, Lee JH, Neelsen KJ, Mund A, Jensen LJ, Paull TT, Mann M, Lukas J., “Homology-directed repair protects the replicating genome from metabolic assaults”, Dev Cell., 56(4):461-477. (2021)
- 4. Cirotti C, Rizza S, Giglio P, Poerio N, Allega MF, Claps G, Pecorari C, Lee JH, Benassi B, Barilà D, Robert C, Stamler JS, Cecconi F, Fraziano M, Paull TT, Filomeni G., “Redox activation of ATM enhances GSNOR translation to sustain mitophagy and tolerance to oxidative stress”, EMBO Rep., 22(1):e50500. (2021)
- 5. Milanovic M, Houghton LM, Menolfi D, Lee JH, Yamamoto K, Li Y, Lee BJ, Xu J, Estes VM, Wang D, Mckinnon PJ, Paull TT, Zha S., “The Cancer-Associated ATM R3008H Mutation Reveals the Link between ATM Activation and Its Exchange”, Cancer Res., 81(2):426-437. (2021)
- 6. Ryu SW, Stewart R, Pectol DC, Ender NA, Wimalarathne O, Lee JH, Zanini CP, Harvey A, Huibregtse JM, Mueller P, Paull TT., “Proteome-wide identification of HSP70/HSC70 chaperone clients in human cells”, PLoS Biol., 18(7):e3000606. (2020)
- 7. Lee JH, Paull TT., “Mitochondria at the crossroads of ATM-mediated stress signaling and regulation of reactive oxygen species”, Redox Biol., 32:101511. (2020)
- 8. Makharashvili N, Arora S, Yin Y, Fu Q, Wen X, Lee JH, Kao CH, Leung JW, Miller KM, Paull TT., “Sae2/CtIP prevents R-loop accumulation in eukaryotic cells”, Elife., 7:e42733. (2018)
- 9. Johnson TE, Lee JH, Myler LR, Zhou Y, Mosley TJ, Yang SH; Bio-Bricks for Molecular Machines FRI Stream, Uprety N, Kim J, Paull TT., “Homeodomain Proteins Directly Regulate ATM Kinase Activity”, Cell Rep., 24(6):1471-1483. (2018)
- 10. Zhang Y, Lee JH, Paull TT, Gehrke S, D'Alessandro A, Dou Q, Gladyshev VN, Schroeder EA, Steyl SK, Christian BE, Shadel GS., “Mitochondrial redox sensing by the kinase ATM maintains cellular antioxidant capacity”, Sci Signal., 11(538):eaaq0702. (2018)
- 11. Lee JH, Mand MR, Kao CH, Zhou Y, Ryu SW, Richards AL, Coon JJ, Paull TT, “ATM directs DNA damage responses and proteostasis via genetically separable pathways”, Sci Signal., 11(512). (2018)
- 12. Hewitt SL, Wong JB, Lee JH, Nishana M, Chen H, Coussens M, Arnal SM, Blumenberg LM, Roth DB, Paull TT, Skok JA, “The Conserved ATM Kinase RAG2-S365 Phosphorylation Site Limits Cleavage Events in Individual Cells Independent of Any Repair Defect”, Cell Rep., 21(4):979-993. (2017)
- 13. Deshpande RA, Lee JH, Paull TT, “Rad50 ATPase activity is regulated by DNA ends and requires coordination of both active sites”, Nucleic Acids Res., 45(9):5255-5268. (2017)
- 14. Zhou Y, Lee JH, Jiang W, Crowe JL, Zha S, Paull TT, “Regulation of the DNA Damage Response by DNA-PKcs Inhibitory Phosphorylation of ATM”, Mol Cell., 65(1):91-104. (2017)
- 15. Deshpande RA, Lee JH, Arora S, Paull TT, “Nbs1 Converts the Human Mre11/Rad50 Nuclease Complex into an Endo/Exonuclease Machine Specific for Protein-DNA Adducts”, Mol Cell., 64(3):593-606. (2016)
- 16. Deshpande RA, Williams GJ, Limbo O, Williams RS, Kuhnlein J, Lee JH, Classen S, Guenther G, Russell P, Tainer JA, Paull TT, “ATP-driven Rad50 conformations regulate DNA tethering, end resection, and ATM checkpoint signaling”, EMBO J., 35(7):791. (2016)
- 17. Zhang J, Tripathi DN, Jing J, Alexander A, Kim J, Powell RT, Dere R, Tait-Mulder J, Lee JH, Paull TT, Pandita RK, Charaka VK, Pandita TK, Kastan MB, Walker CL, “ATM functions at the peroxisome to induce pexophagy in response to ROS”, Nat Cell Biol. 17(10):1259-1269. (2015)
- 18. Lee JH, Guo Z, Myler LR, Zheng S, and Paull TT, “Direct activation of ATM by resveratrol under oxidizing conditions”, PLoS One 9(6):e97969. (2014)
- 19. Makharashvili N, Tubbs AT, Yang S-H, Wang H, Barton O, Zhou Y, Deshpande RA, Lee JH, Lobrich M, Sleckman BP, Wu X, and Paull TT, “Catalytic and non-catalytic roles of CtIP endonuclease in double strand break end resection.”, Mol Cell. 54(6):1022-33. (2014)
- 20. Paull TT and Lee JH, “Rad17, the clamp loader that loads more than clamps.”, EMBO J. 33(8): 783-5 (2014)
- 21. Deshpande RA, Williams GJ, Limbo O, Williams RS, Kuhnlein J, Lee JH, Classen S, Guenther G, Russell P, Tainer JA, Paull TT, “ATP-driven Rad50 conformations regulate DNA tethering, end resection, and ATM checkpoint signaling.”, EMBO J. 33(5):482-500 (2014)
- 22. Bowen C, Ju JH, Lee JH, Paull TT, Gelmann EP, “Functional activation of ATM by the prostate cancer suppressor NKX3.1.”, Cell Rep. 4(3):516-29. (2013)
- 23. Lee JH, Mand MR, Deshpande RA, Kinoshita E, Yang SH, Wyman C, Paull TT, “Ataxia Telangiectasia-Mutated (ATM) kinase activity is regulated by ATP-driven conformational changes in the Mre11/Rad50/Nbs1 (MRN) complex”, J Biol Chem. 3;288(18):12840-51. (2013)
- 24. Gatei M, Jakob B, Chen P, Kijas AW, Becherel OJ, Gueven N, Birrell G, Lee JH, Paull TT, Lerenthal Y, Fazry S, Taucher-Scholz G, Kalb R, Schindler D, Waltes R, Dörk T, Lavin MF, “ATM protein-dependent phosphorylation of Rad50 protein regulates DNA repair and cell cycle control”, J Biol Chem. 286(36):31542-56. (2011)
- 25. Demogines A, East AM, Lee JH, Grossman SR, Sabeti PC, Paull TT, Sawyer SL, “Ancient and recent adaptive evolution of primate non-homologous end joining genes”, PLoS Genet. 21;6(10):e1001169. (2010)
- 26. Lee JH, Goodarzi AA, Jeggo PA, Paull TT, “53BP1 promotes ATM activity through direct interations with the MRN complex”, EMBO J. 3;29(3):574-85. (2010)
- 27. Daniel JA, Pellegrini M, Lee JH, Paull TT, Feigenbaum L, Nussenzweig A., “Multiple autophosphorylation sites are dispensable for murine ATM activation in vivo”, J Cell Biol. 1;183(5):777-83. (2008)
- 28. Dupré A, Boyer-Chatenet L, Sattler RM, Modi AP, Lee JH, Nicolette ML, Kopelovich L, Jasin M, Baer R, Paull TT, Gautier J., “A forward chemical genetic screen reveals an inhibitor of the Mre11-Rad50-Nbs1 complex”, Nat Chem Biol. 4(2):119-25. (2008)
- 29. Lee JH and Paull TT, “Activation and regulation of ATM kinase activity in response to DNA double-strand breaks”, Oncogene, 26(56):7741-8. (2007)
- 30. Hunt CR, Pandita RK, Laszlo A, Higashikubo R, Agarwal M, Kitamura T, Gupta A, Rief N, Horikoshi N, Baskaran R, Lee JH, Lobrich M, Paull TT, Roti Roti JL, Pandita TK., “Hyperthermia activates a subset of ataxia-telangiectasia mutated effectors independent of DNA strand breaks and heat shock protein 70 status”, Cancer Res. 1;67(7):3010-7 (2007)
- 31. Bhaskara V, Dupré A, Lengsfeld B, Hopkins BB, Chan A, Lee JH, Zhang X, Gautier J, Zakian V, Paull TT, “Rad50 adenylate kinase activity regulates DNA tethering by Mre11/Rad50 complexes”, Mol Cell. 9;25(5):647-61. (2007)
- 32. Lee JH and Paull TT, “Purification and biochemical characterization of ATM and MRN”, Methods Enzymol., Vol 408. (2006)
- 33. Paull TT and Lee JH, “The Mre11/Rad50/Nbs1 complex and its role as a DNA double-strand break sensor for ATM”, Cell Cycle, 4(6):737-740. (2005)
- 34. Lee JH and Paull TT, “The Mre11/Rad50/Nbs1 complex is the DNA double-strand break sensor for ATM”, Science 308:551-554. (2005)
- 35. Lee JH and Paull TT, “Direct activation of the ATM protein kinase by the Mre11/Rad50/Nbs1 complex”, Science 304:93-96. (2004)
- 36. Lee JH, Ghirlando R, Bhaskara V, Hoffmeyer MR, Gu J, Paull TT, “Regulation of Mrell/Rad50 by Nbs1”, J. Biol. Chem. 278:45171-45181. (2003)
- 37. Lee JH and Han HU, “Periodical Changes of RNA and Protein Syntheses during the Germination of Streptomyces coelicolor”, Kor. J. Microbiol. 33:7-14. (1997)