ALTering cancer by triggering telomere replication stress through the stabilization of promoter G-quadruplex in SMARCAL1

Most of the human cancers are dependent on telomerase to extend the telomeres. But [~]10% of all cancers use a telomerase-independent, homologous recombination mediated pathway called alternative lengthening of telomeres (ALT). Due to poor prognosis, the ALT status is not being considered yet in the diagnosis of cancer. No such specific treatment is available till date for ALT cancers. ALT positive cancers are dependent on replication stress to deploy DNA repair pathways to the telomeres to execute homology recombination mediated telomere extension. SMARCAL1 (SWI/SNF related, matrix-associated, actin-dependent regulator of chromatin, subfamily A-like 1) is associated with the ALT telomeres to resolve replication stress thus providing telomere stability. Thus, the dependency on replication stress regulatory factors like SMARCAL1 made it a suitable therapeutic target for the treatment of ALT positive cancers. In this study, we found a significant downregulation of SMARCAL1 expression by stabilizing the G-quadruplex (G4) motif found in the promoter of SMARCAL1 by potent G4 stabilizers, like TMPyP4 and BRACO-19. SMARCAL1 downregulation led towards the increased localization of PML (promyelocytic leukaemia) bodies in ALT telomeres and triggered the formation of APBs (ALT-associated promyelocytic leukaemia bodies) in ALT positive cell lines, thus increasing telomere replication stress and DNA damage at genomic level. Induction of replication stress and hyper recombinogenic phenotype in ALT cells mediated by G4 stabilizing molecules already highlighted their possible application as a new therapeutic window to target ALT-positive tumors. In accordance with this, our study will also provide a valuable insight towards the development of G4 based ALT-therapeutics targeting SMARCAL1.