Catalytic Functions of RECQ1 Helicase Are Important in Defying Genomic Stress and Maintaining Cell Proliferation

RecQ helicases are an important class of DNA repair proteins with critical roles in genome maintenance. RECQ1, a structure‐specific DNA helicase and the most abundant RecQ homolog in humans, is frequently upregulated in rapidly proliferating cells and has dual roles in genome maintenance and transcription regulation. RECQ1's function as well as expression levels modulates patient survival and response to anti‐cancer therapy. More recently germline mutations in RECQ1 have been linked to breast cancer susceptibility. However, the mechanism by which altered RECQ1 expression or mutations in functional domains of RECQ1 modulate response to chemotherapy and increase cancer risk is unclear. Our study aimed at generating a RECQ1 knockout cell line using CRISPR‐Cas9 technology to investigate phenotypes of cells that lack RECQ1 expression completely or express breast cancer risk associated RECQ1 mutants in an isogenic background. Our results demonstrate that we have successfully generated a human RECQ1 knockout MDA‐MB‐231 breast cancer cell line using the CRIPSR‐Cas9 technique which recapitulates previously established phenotypes of RECQ1 knockdown resulting in reduced cell proliferation, growth and migration as well as increased sensitivity to camptothecin. We further demonstrate that the missense mutations in the evolutionarily conserved residues within the catalytic core of RECQ1 that predispose individuals to breast cancer, also lead to impaired cell proliferation, increased sensitivity to replication stress and accumulation of spontaneous DNA damage indicating that defective helicase functions of RECQ1 may eventually contribute to genomic instability and drive cancer progression.Support or Funding InformationThis work was funded by the NIGMS/NIH grant SC1GM093999 to Sudha SharmaThis abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.