There are no popularity contests for
proteins, but a prevalent protein called ubiquitin drew quite a
following after three scientists received the 2004 Nobel Prize in Chemistry for discovering its role in mediating protein degradation.
That ground-breaking research on ubiquitination was conducted in the
1970s and ’80s, and it has since been discovered that this small protein
plays a big role in cell biology, including how the human body deals
with internal and external attacks on its DNA.
However, while the essential roles of ubiquitin have received a lot
of attention in the decade since the Nobel was awarded, the reverse of
ubiquitination, or deubiquitination, is less well understood.
Now, a group of researchers led by Zhihao Zhuang, associate professor in the Department of Chemistry and Biochemistry
at the University of Delaware, has discovered that a deubiquitinase (or
DUB) complex, USP1-UAF1, may be a key regulator of the DNA damage
response and a target for overcoming resistance to platinum-based
anticancer drugs. Their findings were published in the online version of
Nature Chemical Biology on Feb. 16.
Our DNA is under constant attack by UV light, radiation, industrial
carcinogens, and other environmental factors, as well as by endogenous
processes such as oxidation and hydrolysis. But our bodies also have
ways to repair that damage or to tolerate it temporarily until a repair
strategy kicks in.
Zhuang’s research group is particularly interested in a DNA damage
tolerance mechanism known as translesion synthesis (TLS), in which
enzymes called TLS polymerases synthesize DNA over the damaged
nucleotide bases, followed by normal replication after the lesion.
The problem is that while TLS polymerases are generally good guys,
they also have a dark side — they have been implicated in making cancer
cells resistant to certain cancer drugs, including cisplatin, which is
often used to treat testicular, bladder, and ovarian cancers that have
spread.
“Cancer drugs like cisplatin work by damaging DNA and thereby
preventing cancer cells from replicating the genomic DNA and dividing,”
Zhuang explains. “However, cancer cells quickly develop resistance to
cisplatin, and we and other researchers suspect that a polymerase known
as Pol η is involved in overcoming cisplatin-induced lesions.”
So while Pol η is a good guy under normal circumstances — in effect,
paving the way over DNA potholes until the road levels out on the other
side — it becomes a bad guy when the smooth road enables cancer cells to
keep traveling.
Now, Zhuang and his team have discovered a new molecule, ML323, that
can inhibit processes, such as TLS, that may be hijacked by cancer cells
to overcome the roadblocks on genomic DNA.
“Using ML323, we studied the cellular response to DNA damage and
revealed new insights into the role of deubiquitination in both the TLS
pathway and another one called the Fanconi anemia, or FA, pathway,”
Zhuang says. “We’re very encouraged by the fact that a single molecule
is effective at inhibiting the USP1-UAF1 DUB complex and disrupting two essential DNA damage tolerance pathways.”
The finding may give clinicians a new weapon in the arsenal against cancer.
“We exposed lung cancer cells to cisplatin alone and to a combination
of cisplatin and ML323, and we achieved close to an order of magnitude
reduction in EC50, a common measure of the potency of
small-molecule drugs, when the combination was used,” Zhuang says. “This
tells us that the inhibitor effectively restores the ability of
cisplatin to fight cancer cells.”
“Cancer treatment is increasingly moving to combination therapies to
make it more effective and less toxic to normal cells,” he adds. “I
think our findings from this work indicate that the USP1-UAF1 DUB
inhibitor not only shows promise in fighting cancer but also can help us
in investigating the complex biology of DNA damage responses.”
The Nature Chemical Biology paper has been selected as a
highlight by several journals since its publication online last month,
and many people have contacted Zhuang to express interest in the work.
The paper, “A Selective USP1–UAF1 Inhibitor Links Deubiquitination to DNA Damage Responses,” was the result of collaborative work between Zhuang’s lab at UD and a research group led by David Maloney at the National Institutes of Health National Center for Advancing Translational Sciences.
The coauthors also included researchers from the University of California, Riverside, the State Key Laboratory of Food Science and Technology at Nanchang University in China, and the Laboratory of Macromolecular Analysis and Proteomics at Albert Einstein College of Medicine in New York.
