Ching-Shyi Wu

Cancer is an evolutionary disease fueled by genomic instability. Mammalian genome integrity is guarded by a complex DNA damage signaling and repair network, termed the DNA damage response (DDR). ATR is a pivotal kinase that regulates cell cycle checkpoints and promotes DNA repair processes via the ATR-Chk1 signaling. In addition to phosphorylation events, other types of post-translational modifications (PTMs), such as SUMOylation, ubiquitination, and acetylation are also critical to the ATR-mediated DDR. Understanding how the ATR signaling and PTM mechanisms are coordinated to maintain genomic stability will provide insights into cellular transformation and identify novel therapeutic targets.

The SUMO pathway in the ATR-Chk1 signaling

The ATR-Chk1 signaling pathway is essential for regulating the DDR and suppressing replication stress in the absence of exogenous threats. We showed that the SUMO pathway directly regulates DNA damage signaling through the ATR-Chk1 axis. Using approaches of cellular and molecular biology and protein biochemistry, one of my current research focuses is to dissect the mechanism by which SUMO pathway regulates DDR and replicative stress via modulating the ATR-Chk1 signaling.

Developing novel therapies for treating SUMO-deficient cancers

Inhibition of the DDR greatly sensitizes cancers to chemo- and radio- therapies, since most therapies induce DNA damage to kill cancers. The protein level of SUMO E3 ligases, for example, PIAS3, is commonly reduced or not detected in certain types of cancers, and those low-PIAS3 cancers are more resistant to current chemotherapies. We have shown that PIAS3 is functionally important in ATR signaling and cancer cells with the PAIS3 knockdown by siRNA are more sensitive to inhibitors of PARP and ATR. We hope to exploit SUMO pathway as prognostic markers and develop novel therapies using inhibitors of PARP and ATR to target SUMO-deficient cancers.  

近期代表著作：

1] The SUMO Ligase PIAS3 Primes ATR for Checkpoint Activation. J Bio Chem 2016, 291:279-90.    [Abstract]

2] SUMOylation of ATRIP Potentiates the DNA Damage Signaling by Boosting Multiple Protein Interactions in the ATR Pathway. Genes & Dev 2014, 28:1472-1484. [Abstract]

3] PRP19 Transforms into a Sensor of RPA-ssDNA after DNA Damage and Drives ATR Activation via a Ubiquitin-Mediated Circuitry. Mol Cell 53:1-12. [Abstract]

This article is the focus of a research highlight in Nat Rev Mol Cell Biol 2014, 15(2):76.

4] Targeted Sister Chromatid Cohesion by Sir2. PLOS Genet 2011, 7(2): e1002000. doi:10.1371/journal.pgen.1002000.  [Abstract]

5] Targeting of Cohesin by Transcriptionally Silent Chromatin. Genes & Dev 2005, 19, 3031-3042.  [Abstract]

This work is the focus of a dedicated review in Genes & Dev (2006) 20:132-173.

6] Cordyceps sinensis and its Fractions Stimulated MA-10 Mouse Leydig Tumor Cell Steroidogenesis. J Androl 2001, 22, 831-837.  [Abstract]

7] Melatonin Inhibits the Expression of Steroidogenic Acute Regulatory Protein and Steroidogenesis in MA-10 Cells. J Androl 2001, 22, 245-254.  [Abstract]

Uncovering roles of post-translational modifications, such as SUMOylation, ubiquitination, and acetylation in the genome instability and tumorigenesis, and exploiting synthetic lethality for cancer therapy.