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A key cellular response to DNA double-strand breaks (DSBs) is 5'-to-3' DSB resection by nucleases to generate regions of ssDNA that then trigger cell cycle checkpoint signaling and DSB repair by homologous recombination (HR). Here, we reveal that in the absence of exonuclease Exo1 activity, deletion or mutation of the Saccharomyces cerevisiae RecQ-family helicase, Sgs1, causes pronounced hypersensitivity to DSB-inducing agents. Moreover, we establish that this reflects severely compromised DSB resection, deficient DNA damage signaling, and strongly impaired HR-mediated repair. Furthermore, we show that the mammalian Sgs1 ortholog, BLM--whose deficiency causes cancer predisposition and infertility in people--also functions in parallel with Exo1 to promote DSB resection, DSB signaling and resistance to DSB-generating agents. Collectively, these data establish evolutionarily conserved roles for the BLM and Sgs1 helicases in DSB processing, signaling, and repair.

Original publication

DOI

10.1101/gad.503108

Type

Journal article

Journal

Genes Dev

Publication Date

15/10/2008

Volume

22

Pages

2767 - 2772

Keywords

Bloom Syndrome, Bone Neoplasms, DNA Breaks, Double-Stranded, DNA Helicases, DNA Repair, Exodeoxyribonucleases, Humans, Microscopy, Fluorescence, Mutation, Osteosarcoma, Plasmids, RNA, Small Interfering, RecQ Helicases, Recombination, Genetic, Saccharomyces cerevisiae, Saccharomyces cerevisiae Proteins, Transfection, Tumor Cells, Cultured