A new study at Tel Aviv University found that an elevated level of protein called ubiquilin-4 is a new biomarker of genomic instability. The study found that ubiquilin 4 is involved in protecting the genome from DNA damage, while excessive ubiquilin 4 is harmful. When the number of ubiquilin 4 in tumor cells increases, these cells are more susceptible to genomic instability, accelerating tumor development and making them resistant to commonly used cancer treatments.
UBQLN4 deficiency leads to increased sensitivity to genotoxic stress and delayed DNA double-strand break (DSB) repair. The proteasomal shuttle factor UBQLN4 is phosphorylated
by ATM and interacts with ubiquitylated MRE11 to mediate early steps of homologous recombination-mediated DSB repair (HRR). Loss of UBQLN4 leads to chromatin retention of MRE11, promoting non-physiological HRR activity in vitro and in vivo.
Conversely, UBQLN4 overexpression represses HRR and favors non-homologous end joining. Moreover, the researchers find UBQLN4 overexpressed in aggressive tumors. In line with an HRR defect in these tumors, UBQLN4 overexpression is 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 new biomarker provides new key information about tumor staging and grading and how patients respond to treatment," the researchers said. "Tumors with high ubiquilin 4 levels may be more resistant to radiation and chemotherapy than normal levels of tumors. But the good news is that they may respond better to other types of cancer treatment. Obviously, this is the clinician and Important information the patient needs. We hope that this discovery will provide a new tool for tumor classification, prognosis, and treatment design, emphasizing the broader impact of genomic stability on our health."
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