BLM and FANCJ role in the response to G-quadruplex-dependent telomeric replicative stress

DNA G-quadruplexes (G4s) spontaneously arise in guanine-rich regions such as telomeres. Although G4s regulate essential biological process, their persistence can interfere with DNA metabolism and induce replication stress (RS). Helicases such as BLM and FANCJ play key roles in resolving G4 structures to maintain genome stability. Our investigation delves into how BLM and FANCJ respond to telomeric RS induced by the telomeric G4 ligand, RHPS4. To examine their individual and combined functions, we employed CRISPR/Cas9 to deplete BLM and siRNA to silence FANCJ in U251MG glioblastoma cells. Our results revealed a functional interplay between the two helicases: RHPS4 treatment led to increased FANCJ protein levels and telomeric recruitment in both wild-type and BLM-/- cells. Notably, FANCJ depletion resulted in heightened sensitivity to RHPS4, accompanied by increased telomere dysfunction and DNA damage, particularly in the absence of BLM. These findings underscore a compensatory role for FANCJ in maintaining telomere integrity under RS and highlight its potential as a therapeutic target for enhancing the efficacy of G4-stabilizing agents in cancer treatment. Functional dissection of G-quadruplex–induced replication stress uncovers complementary telomeric roles of BLM and FANCJ helicases and identifies FANCJ loss as a vulnerability that increases telomere damage and sensitivity to G4-stabilizing agents.