Sheau-Yann Shieh

Genome stability is maintained by intricate networks of cell cycle checkpoint proteins. In response to genotoxic stress, either extrinsic such as ionizing radiation-induced DNA breaks or intrinsic such as oxidative damage, a cascade of signaling events are initiated to arrest the cell cycle, eliminate damaged cells, or to repair the damage. Defects in these responses often lead to accumulation of mutations and development of cancers. Our studies are focused on targets of the checkpoint pathways involving the tumor suppressors and the checkpoint kinases CHK1 and CHK2, of which mutations are associated with human cancers. Our main goals are to decipher the molecular basis of checkpoint control by these proteins, their functional relationship with DNA repair and genome maintenance, and the impacts on tumorigenesis.

• Graduate Institute of Life Sciences, National Defense Medical Center, Taipei, Taiwan
• Molecular Medicine, National Yang Ming Chiao Tung University
• Graduate Institute of Microbiology, National Taiwan University College of Medicine, Taipei, Taiwan, 08/09 ~ 06/20

• Grant review National Science Council (NSC)/Ministry of Science and Technology (MOST) 2003-present
• Journal reviewer

Biomedical Reports, BMC Biology, Cancer Letters, Cell Death and Disease, Cell Reports, Current Topics in Medicinal Chemistry, Disease Markers, EMBO Molecular Medicine, Experimental and Therapeutic Medicine, Experimental Hematology & Oncology, International Journal of Biological Sciences, International Journal of Molecular Medicine, International Journal of Oncology, International Journal of Radiation Oncology, Biology, Physics, iScience, Journal of Biomedical Science, Journal of Dermatological Science, Journal of Hematology & Oncology, Kaohsiung Journal of Medical Sciences, Letters in Drug Design & Discovery, Medicinal Chemistry, Molecular and Clinical Oncology, Molecular Carcinogenesis, Molecular Medicine Reports, Nucleic Acids Research, Nature Communications, Oncogene, Oncogenesis, Oncology Letters, Oncology Report, PLOS Genetics, Scientific Reports

• Committee (IBMS)

2007 Core Facility; Education

2008 Core Facility; Education; Proteomics

2009 Appointment, Promotion &Tenure; Education; Proteomics

2010 Appointment, Promotion &Tenure; Personnel; Education

2011 Chair, Education

2012 Chair, Education

2013 Chair, Education

2018-present Animal

• Coordinator, Taiwan International Graduate Program in Molecular Medicine, Academia Sinica 09/15~10/18

Past trainees:

Jen-Hsuan Wei (M.S., National Taiwan University) 06/02

Te-Ping Sun (Ph.D, National Defense Medical College) 06/09

Yi-Fu Huang (Ph.D, National Tsing Hua University) 06/09

Fu-Fei Hsu (Ph.D, National Yang-Ming University) 06/10

Fu-Fei Hsu (Post-doctoral fellow, Academia Sinica) 07/10 ~ 11/11

Yu-Che Cheng (Ph.D, National Defense Medical College) 06/13

Cheng-Cheng Yu (Ph.D, National Taiwan University) 12/15

Pei-Chin Hsu (Ph.D, National Defense Medical College) 12/18

Rajaneesh Karimpurath Gopinath (Post-doc fellow, Academia Sinica) 04/16 ~ 01/19

Al Nayem Chowdhury (Ph.D, TIGP Academia Sinica) 07/22

Al Nayem Chowdhury (Post-doc fellow, Academia Sinica) 08/22 ~05/23

Current trainees:

Yu-Che Cheng (Post-doc fellow, Academia Sinica), 06/13 ~ present

Jack Dalit Acedera (Ph.D. candidate, TIGP Academia Sinica), 8/18 ~ present

Selvi Rahmawati (Ph.D. candidate, TIGP Academia Sinica), 1/23 ~ present

• 2006 Academia Sinica Young Investigator Award

1. Cheng YC, Acedera JD, Li YJ, Shieh SY*. 2024. “A   keratinocyte-adipocyte signaling loop is reprogrammed by loss of BTG3 to   augment skin carcinogenesis.” Cell Death Differ. doi:   10.1038/s41418-024-01304-7. Epub ahead of print

2. Chowdhury MAN, Wang SW, Suen CS, Hwang MJ, Hsueh   YA, Shieh SY*. 2022. “JAK2-CHK2 signaling safeguards the integrity of the   mitotic spindle assembly checkpoint and genome stability.” Cell Death Dis.  13(7), 619.

3. Cheng YC, Shieh, SY. 2021. “Determination of   CHK1 Cellular Localization by Immunofluorescence Microscopy.” In: Manfredi   J.J. (eds) Cell Cycle Checkpoints. Methods in Molecular Biology, vol 2267.   Humana, New York, NY. https://doi.org/10.1007/978-1-0716-1217-0_1

4. Cheng YC†, Chiang HY†,   Cheng SJ†, Chang HW, Li YJ, Shieh SY*. 2020. “Loss of the tumor suppressor   BTG3 drives a pro-angiogenic tumor microenvironment through HIF-1 activation.”   Cell Death Dis. 11, 1046. (†equal contributions)

5. Hsu PC, Gopinath RK, Hsueh YA, Shieh SY*. 2019. CHK2-mediated regulation of   PARP1 in oxidative DNA damage response. Oncogene   38, 1166-1182.

6. Cheng YC, Shieh SY*. 2018. “Deubiquitinating   enzyme USP3 controls CHK1 chromatin association and activation.”, Proc   Natl Acad Sci U S A. 115(21), 5546-5551.

7. Chang CH*, Kuo CJ, Ito T, Su YY, Jiang ST, Chiu   MH, Lin YH, Nist A, Mernberger M, Stiewe T, Ito S, Wakamatsu K, Hsueh YA,  Shieh SY, Snir-Alkalay I, Ben-Neriah Y. 2017. “CK1alpha ablation in   keratinocytes induces p53-dependent, sunburn-protective skin   hyperpigmentation.”, Proc Natl Acad Sci U S A. 114(38), E8035-E8044.

8. Yu ZC, Huang YF, Shieh SY*. 2016. “Requirement   for human Mps1/TTK in oxidative DNA damage repair and cell survival through   MDM2 phosphorylation.”, Nucleic Acids Res 44(3), 1133-1150.

9. Cheng YC, Chen PH, Chiang HY, Suen CS, Hwang MJ,   Lin TY, Yang HC, Lin WC, Lai PL, Shieh SY*. 2015. “Candidate tumor suppressor   B-cell translocation gene 3 impedes neoplastic progression by suppression of   AKT.” Cell Death Dis., 6, e1584.

10. Yeh CW, Yu ZC, Chen PH, Cheng YC, Shieh SY*.   2014. “Phosphorylation at Threonine 288 by Cell Cycle Checkpoint Kinase 2   (CHK2) Controls Human Monopolar Spindle 1 (Mps1) Kinetochore Localization.”, J   Biol Chem. 289(22), 15319-15327.

11. Cheng YC, Lin TY, Shieh SY*. 2013. “Candidate   tumor suppressor BTG3 maintains genomic stability by promoting Lys63-linked   ubiquitination and activation of the checkpoint kinase CHK1.”, Proc Natl   Acad Sci U S A. 110(15), 5993-5998.

12. Lin TY, Cheng YC, Yang HC, Lin WC, Wang CC, Lai   PL, Shieh SY*. 2012. “Loss of the candidate tumor suppressor BTG3 triggers   acute cellular senescence via the ERK-JMJD3-p16(INK4a) signaling axis”, Oncogene  31(27), 3287-3297.

13. Park JH*, Smith RJ, Shieh SY, Roeder RG.   2011. “The GAS41-PP2Cbeta complex dephosphorylates p53 at serine 366 and   regulates its stability.”, J Biol Chem. 286(13), 10911-10917.

14. Lai MC, Chang WC, Shieh SY, Tarn WY*.   2010. “DDX3 regulates cell growth through translational control of cyclin   E1.”, Mol Cell Biol. 30(22), 5444-5453.

15. Shieh SY*. 2010. “Dancing with p53: The role of   p38MAPK in mitosis of p53-deficient tetraploid cells.”, Cell Cycle,   9(14), 2712.

16. Hsu FF, Lin TY, Chen JY, Shieh SY*, 2010,   “p53-Mediated transactivation of LIMK2b links actin dynamics to cell cycle   checkpoint control.”, Oncogene 29(19), 2864-2876.)

17. Sun TP, Shieh SY*. 2009. “Human FEM1B is   required for Rad9 recruitment and CHK1 activation in response to replication   stress”, Oncogene 28(18), 1971-1981.

18. Yeh YH, Huang YF, Lin TY and Shieh SY*. 2009.   “The cell cycle checkpoint kinase CHK2 mediates DNA damage-induced stabilization   of TTK/hMps1”, Oncogene 28(10), 1366-1378.

19. Kuo PC, Tsao YP, Chang HW, Chen PH, Huang CW,   Lin ST, Weng YT, Tsai TC, Shieh SY, Chen SL*. 2009. “Breast cancer   amplified sequence 2, a novel negative regulator of the p53 tumor   suppressor.”, Cancer Res. 69(23), 8877-8885.

20. Huang YF, Chang MDT, Shieh SY*. 2009. “TTK/hMps1   mediates the p53-dependent postmitotic checkpoint by phosphorylating p53 at   Thr18”, Mol. Cell. Biol., 29, 2935-2944.

21. Chou WC, Wang HC, Wong FH, Ding S, Wu PE, Shieh   SY*, Shen CY*. 2008. “Chk2-dependent phosphorylation of XRCC1 in the DNA   damage response promotes base excision repair”, EMBO J. 27, 3140-3150.

22. Ou YH, Chung PH, Hsu FF, Sun TP, Chang WY, Shieh   SY*. 2007. “The candidate tumor suppressor BTG3 is a transcriptional target   of p53 that inhibits E2F1”, EMBO J. 26(17), 3968-3980.

23. Wang HC, Chou WC, Shieh SY, Shen CY*.   2006. “Ataxia telangiectasia mutated and checkpoint kinase 2 regulate BRCA1   to promote the fidelity of DNA end-joining”, Cancer Res. 66,   1391-1400.

24. Ou YH, Chung PH, Sun TP, Shieh SY*. 2005. “p53   C-Terminal Phosphorylation by CHK1 and CHK2 Participates in the Regulation of   DNA-Damage-induced C-Terminal Acetylation”, Mol Biol Cell 16,   1684-1695.

25. Wei JH, Chou YF, Ou YH, Ye YS, Tyan SW, SunYP,   Shen CY, Shieh SY*. 2005. “TTK/hMps1 participates in the regulation of DNA   damage checkpoint response by phosphorylating CHK2 on threonine 68”, J   Biol Chem. 280, 7748-7757.

26. Gottifredi V, Shieh SY, Taya Y, Prives C*.   2001. “p53 accumulates but is functionally impaired when DNA synthesis is   blocked”, Proc Natl Acad Sci U S A.  98, 1036-1041.

27. Gottifredi V, Karni-Schmidt O, Shieh SY, Prives   C*. 2001. “p53 down-regulates CHK1 through p21 and the retinoblastoma   protein”, Mol Cell Biol. 21, 1066-1076.

28. Gottifredi V, Shieh SY, Prives C*. 2000.   “Regulation of p53 after different forms of stress and at different cell   cycle stages”, Cold Spring Harb Symp Quant Biol. 65, 483-488.

29. Shieh SY, Ahn   J, Tamai K, Taya Y, Prives C*. 2000, “The human homologs of checkpoint   kinases Chk1 and Cds1 (Chk2) phosphorylate p53 at multiple DNA   damage-inducible sites”, Genes Dev. 14, 289-300.

30. Tibbetts RS, Brumbaugh KM, Williams JM, Sarkaria   JN, Cliby WA, Shieh SY, Taya Y, Prives C, Abraham RT*. 1999. “A role   for ATR in the DNA damage-induced phosphorylation of p53”, Genes Dev.  13, 152-157.

31. Shieh SY,   Taya Y, Prives C*. 1999. “DNA damage-inducible phosphorylation of p53 at   N-terminal sites including a novel site, Ser20, requires tetramerization”, EMBO   J. 18, 1815-1823.

32. de Stanchina E, McCurrach ME, Zindy F, Shieh   SY, Ferbeyre G, Samuelson AV, Prives C, Roussel MF, Sherr CJ, Lowe SW*.   1998. “E1A signaling to p53 involves the p19(ARF) tumor suppressor”, Genes   Dev. 12, 2434-2442.

33. Banin S, Moyal L, Shieh SY, Taya Y,   Anderson CW, Chessa L,. Smorodinsky NI, Prives C, Reiss Y, Shiloh Y*, Ziv Y.   1998. “Enhanced phosphorylation of p53 by ATM in response to DNA damage”, Science  281, 1674-1677.

34. Shieh SY,   Ikeda M, Taya Y, Prives C*, 1997, “DNA damage-induced phosphorylation of p53   alleviates inhibition by MDM2”, Cell 91, 325-334.

35. Ko LJ, Shieh SY, Chen X, Jayaraman L,   Tamai K, Taya Y, Prives C*, Pan ZQ. 1997. “p53 is phosphorylated by   CDK7-cyclin H in a p36MAT1-dependent manner”, Mol Cell Biol. 17,   7220-7229.

36. Cain C, Shieh SY, Prives C*. 1997.   “Signaling to the C-terminus of p53”, editor(s): M Yaniv, J Ghysdael, Oncogenes   as transcriptional regulators. Volume 2: cell cycle regulators and   chromosomal translocation, pp. 63-75, USA: Birkhauser Verlaq.

37. Shieh SY,   Stellrecht CM, Tsai MJ*. 1995. “Molecular characterization of the rat insulin   enhancer-binding complex 3b2. Cloning of a binding factor with putative   helicase motifs.”, J Biol Chem. 270(37), 21503-8.

38. Robinson GL, Peshavaria M, Henderson E, Shieh   SY, Tsai MJ, Teitelman G, Stein R*. 1994. “Expression of the trans-active   factors that stimulate insulin control element-mediated activity appear to   precede insulin gene transcription.”, J Biol Chem. 269(4), 2452-60.

39. Shieh SY,   Tsai MJ*. 1991. “Cell-specific and ubiquitous factors are responsible for the   enhancer activity of the rat insulin II gene.”, J Biol Chem. 266(25),   16708-14.