POLQ mediated end-joining promotes DNA damage tolerance in neuroblastoma

Abstract

Segmental chromosomal alterations, including 11q deletion and 17q gain, are the strongest predictors of pediatric neuroblastoma relapse. These alterations result from unbalanced translocations linked to erroneous DNA repair. Breakpoint sequence analysis suggests that these abnormalities arise through a nonhomologous end-joining mechanism, indicating a potential therapeutic opportunity. While the exact components driving this DNA end-joining process in neuroblastoma remain unknown, polymerase theta-mediated end-joining (TMEJ) has been implicated in other homologous recombination-deficient cancers. Our previous work demonstrated that high-risk neuroblastoma expresses elevated levels of TMEJ components, including DNA Ligase III and Ligase I, while downregulating classical NHEJ factors (DNA Ligase IV and Artemis). Here we show that POLQ, a critical enzyme in TMEJ, is significantly upregulated in neuroblastoma. POLQ knockout impairs proliferation, enhances sensitivity to DNA damaging agents, and reduces tumor growth in vivo. These findings suggest that POLQ facilitates DNA damage tolerance in neuroblastoma and represents a viable therapeutic target.

Keywords

• DNA repair
• POLQ
• Neuroblastoma
• Therapy resistance