Co-deficiency of the BLM and RECQL1 Helicases Causes Synthetic Lethality, Pronounced Replication Stress, and Loss of Chromatid Cohesion

The mechanistic basis for chromosomal instability characteristic of RECQ helicase genetic disorders has been elusive, given the complexity and apparent redundancy of cellular pathways important for genome homeostasis. To characterize the genetic interactions of RECQL1 helicase (recently implicated in the rare hereditary disorder RECON syndrome) essential for genome integrity, we performed an acute depletion RNA interference screen and determined a synthetic lethal interaction of RECQL1 with BLM helicase (linked to the cancer-prone disease Bloom syndrome) in cells exposed to a DNA alkylating agent that induces replication stress. The profound replication stress of cells co-deficient in RECQL1 and BLM was marked by elevated DNA damage and chromosomal instability. Strikingly, RECQL1/BLM co-deficiency induced a novel phenotype of premature sister chromatid separation that could be suppressed by depletion of the cohesion unloader WAPL, suggesting that a threshold of replication stress disrupts cohesion establishment. Primary embryonic fibroblasts from transgenic Recql-/- Blm-/- mice recapitulated the replication stress phenotypes of human cells, and the small intestines of Recql-/- Blm-/- mice showed elevated DNA damage. Our findings highlight the important role of either RECQL1 or BLM when the other is deficient, as is the case for each respective hereditary disorder. Moreover, this study suggests a potentially therapeutic vulnerability of cancers harboring somatic mutations in RECQL1, BLM, or other genome caretakers that function in pathways that confer resistance to replication stress.