UC San Diego

Two cancer predisposition disorders observed in humans, Werner syndrome (WS) and Bloom syndrome (BS), are caused by loss of function of the RecQ helicases WRN or BLM, respectively. BS and WS are characterized by replication defects, hyper-recombination events and chromosomal aberrations, which are hallmarks of cancer. Our lab has shown how inefficient replication of the G-rich telomeric strand contributes to chromosome aberrations in WS cells, demonstrating a link between WRN, telomeres and genomic stability. Here I provide evidence that the BLM RecQ helicase also contributes to chromosome-end maintenance. Chromosome fusions and telomeric defects are elevated in fibroblasts lacking BLM; these aberrations are suppressed by hTERT- mediated telomere elongation, confirming a telomere-specific dysfunction in BS cells. Examination of metaphase chromosomes showed that telomere defects are significantly greater in BLM-deficient cells, similar to observations in cells lacking a functional WRN helicase. Furthermore, loss of both helicases exacerbates telomere defects and chromosome aberrations, indicating that BLM and WRN function independently in telomere maintenance. Fluorescence analysis revealed that BLM localization, particularly its recruitment to telomeres, changes in response to replication dysfunction. WRN deficiency or aphidicolin exposure led to an increase in late- replicating intermediates, observed as BLM-positive ultra- fine bridges (UFBs), particularly UFBs originating from telomeric DNA. I propose that the BLM RecQ helicase (likely in complex with the proteins TOPOIII[alpha], RMI1, RMI2) contributes to telomere maintenance, though most likely in a capacity distinct from WRN RecQ helicase