Telomere fusions derived from POLQ-deficient cells evidence elevated replication stress and skewed DNA repair capacity during crisis

DNA polymerase theta (POLQ) is a principal component of the alternative non-homologous end-joining (ANHEJ) DNA repair pathway that ligates chromosome breaks from both endogenous and exogenous sources of cellular stress. Utilising independent models of DNA polymerase theta (POLQ) insufficiency during telomere-driven crisis, we determined that POLQ-/- cells are resistant to crisis-induced growth deceleration despite sustaining inter-chromosomal telomere fusion frequencies equivalent to wild-type (WT) cells. Responses to extrinsic DNA insults were preserved in POLQ-/- cells and clonal escape was demarcated by the recovery of telomerase expression analogous to WT cells. We observed longer telomere lengths in POLQ-/- than WT cells both pre- and post-crisis, notwithstanding the elevated total telomere erosion, population doublings and telomere fusion rates recorded for the POLQ-deficient cells. We discovered that POLQ stimulates, but is not essential, for sister chromatid fusions and symmetrical amplicons are more sensitive than asymmetrical ones to POLQ deficits. Pertinently, we ascertained greater efficacy of the rediscovered antibiotic POLQ inhibitor, novobiocin, in the modulation of DNA repair activity in cells with atypical POLQ expression.