DNA helicases Sgs1 and BLM promote DNA double-strand break resection

Genes Dev. 2008 Oct 15;22(20):2767-72. doi: 10.1101/gad.503108.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Bloom Syndrome / metabolism
  • Bone Neoplasms / genetics
  • Bone Neoplasms / metabolism
  • Bone Neoplasms / pathology
  • DNA Breaks, Double-Stranded*
  • DNA Helicases / antagonists & inhibitors
  • DNA Helicases / genetics
  • DNA Helicases / metabolism*
  • DNA Repair / drug effects
  • Exodeoxyribonucleases / metabolism
  • Humans
  • Microscopy, Fluorescence
  • Mutation / genetics
  • Osteosarcoma / genetics
  • Osteosarcoma / metabolism
  • Osteosarcoma / pathology
  • Plasmids
  • RNA, Small Interfering / pharmacology
  • RecQ Helicases / antagonists & inhibitors
  • RecQ Helicases / genetics
  • RecQ Helicases / metabolism*
  • Recombination, Genetic
  • Saccharomyces cerevisiae / genetics
  • Saccharomyces cerevisiae / growth & development
  • Saccharomyces cerevisiae / metabolism*
  • Saccharomyces cerevisiae Proteins / antagonists & inhibitors
  • Saccharomyces cerevisiae Proteins / genetics
  • Saccharomyces cerevisiae Proteins / metabolism*
  • Transfection
  • Tumor Cells, Cultured

Substances

  • RNA, Small Interfering
  • Saccharomyces cerevisiae Proteins
  • Exodeoxyribonucleases
  • exodeoxyribonuclease I
  • Bloom syndrome protein
  • SGS1 protein, S cerevisiae
  • DNA Helicases
  • RecQ Helicases