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Characterization of small molecule for ATAD5 destabilizer

Wednesday, November 06, 2013 — Poster Session I

4:00 p.m. – 6:00 p.m.

FAES Academic Center (Upper-Level Terrace)

NHGRI

MOLBIO-8

Authors

  • Y Choi
  • J Fox
  • K Myung

Abstract

Chemotherapeutic and radiation treatments cause a variety of genotoxic insults that lead to cell death in rapidly proliferating cancer cells. We recently reported that human putative tumor suppressor protein, ATAD5 is stabilized in response to almost all genotoxic insults (1). We screened 300,000 compounds to identify small molecule(s) named UT2 that inhibit ATAD5 stabilization in response to DNA damage. In addition to inhibition of ATAD5 stabilization, UT2 blocked general DNA damage responses including RPA32- and CHK1-phosphorylation after UV irradiation. Interestingly, UT2 treatment reduced the protein level of two major protein kinases for DNA damage response; DNA-dependent protein kinase catalytic subunit (DNA-PKcs) and Ataxia Telangiectasia Rad3 related (ATR). It could be due to the destabilization of upstream protein, TEL2, which functions to stabilize the phosphatidylinositol 3-kinase related protein kinase (PIKK) family proteins (including DNA-PKcs and ATR). To understand the molecular mechanisms how UT2 affects DNA repair pathway, we investigated cell viability in cells defective in a DNA repair gene in various DNA repair pathways. UT2 induced cell death in parp1-/- HCT116 cells. Collectively, sensitization of cancer cells by UT2, especially in PARP1-deficient cells suggested that UT2 could be a potential chemotherapeutic agent targeting tumors defective in base excision repair.

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