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Genotoxic stress such
as environmental radiation and chemical mutagens assault genomic integrity
resulting in cancer. Data from the recently completed human genome project
and genetic analyses in both yeast and mammals have strongly implicated
the ubiquitin-proteasome system as a regulator of DNA-damage response
and DNA repair. However, the mechanism by which the ubiquitin-proteasome
system modulates the response to assaults on genomic integrity remains
unknown. We have developed a signal-based, combinatorial functional proteomic
system using approximately 30,000 full-length proteins expressed in
vitro and have applied this cutting-edge technology to systematically
identify genome-wide all proteins ubiquitylated and degraded in response
to DNA damage (e.g., gamma-radiation and Adriamycin). In our initial screening,
we have identified several candidates that are degraded in response to
genotoxic stress. These candidate proteins could function as sensors,
transducers, effectors, and as other regulators of DNA damage-repair pathways.
This novel system has provided us a potent approach to address the mechanism
of tumorigenesis caused by malfunction of ubiquitin-proteasomal machinery
as pertaining to the DNA-damage response and repair. Identification of
ubiquitin-regulated components involved in response to assaults on genomic
integrity could reveal previously unknown targets for anti-cancer therapy.
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