Our DNA is under constant attack. The delicate molecule that contains our genetic information is extremely vulnerable to everything from environmental agents, such as radiation, to the chemicals in the air we breathe and the food we eat. Genome instability can lead to genetic disorders, chronic diseases and a predisposition to cancer.
A new study identifies elevated levels of a protein called ubiquilin-4 (UBQLN4 ) as a new biomarker for genome instability. The study published in Cell finds UBQLN4 takes part in defending the genome from DNA damage, but too much ubiquilin-4 is harmful. When the amount of ubiquilin-4 rises in tumor cells, the cells become more prone to genome instability, accelerating the tumor's progression and making it resistant to commonly used cancer treatments. UBQLN4 overexpression represses homologous recombination-mediated DSB repair (HRR) and favors non-homologous end joining. UBQLN4 overexpression is also associated with PARP1 inhibitor sensitivity. UBQLN4 therefore curtails HRR activity through removal of MRE11 from damaged chromatin and thus offers a therapeutic window for PARP1 inhibitor treatment in UBQLN4-overexpressing tumors.
"This novel biomarker provides new, critical information about the tumor stage and grade, as well as the patient's chances of responding to treatment," says the senior author. "Tumors with high levels of ubiquilin-4 may be more resistant to radiation and some chemotherapies than those with normal levels of this protein. But the good news is that they may also respond better to other types of cancer therapy. Obviously, this is vital information for clinicians and patients.
According to the new research, the body's DNA damage response is key to maintaining genome stability in the face of the constant onslaught of damaging agents. The response is composed of a broad, fine-tuned signaling network involving a standing army of proteins fully dedicated to this mission, as well as reserve proteins recruited temporarily to help resolve genome integrity.
The protein ataxia-telangiectasia mutated (ATM) plays a critical role in the body's DNA damage response, mobilizing an extensive signaling network in response to tears in the long DNA molecule. It causes subtle chemical modifications in many proteins, which temporarily render them reserve proteins and recruits them away from their regular duties to carry out damage control.
"We are constantly searching for new reserve proteins that respond to ATM's call," the senior author says. "Our new study shows that, like many other proteins, ubiquilin-4 is phosphorylated by ATM, and and interacts with ubiquitylated MRE11 to mediate early steps of homologous recombination-mediated DSB repair (HRR)." The researchers also discovered that the UBQLN4 deficiency leads to increased sensitivity to genotoxic stress and delayed DNA double-strand break (DSB) repair. "We hope our findings will provide a new tool for tumor classification, prognosis and treatment design," the senior author concludes. "The research highlights the broader implications of the importance of genome stability for our health."
New biomarker links cancer progression to genome instability
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