DYNLL1 binds to MRE11 to limit DNA end resection in BRCA1-deficient cells

Nature. 2018 Nov;563(7732):522-526. doi: 10.1038/s41586-018-0670-5. Epub 2018 Oct 31.


Limited DNA end resection is the key to impaired homologous recombination in BRCA1-mutant cancer cells. Here, using a loss-of-function CRISPR screen, we identify DYNLL1 as an inhibitor of DNA end resection. The loss of DYNLL1 enables DNA end resection and restores homologous recombination in BRCA1-mutant cells, thereby inducing resistance to platinum drugs and inhibitors of poly(ADP-ribose) polymerase. Low BRCA1 expression correlates with increased chromosomal aberrations in primary ovarian carcinomas, and the junction sequences of somatic structural variants indicate diminished homologous recombination. Concurrent decreases in DYNLL1 expression in carcinomas with low BRCA1 expression reduced genomic alterations and increased homology at lesions. In cells, DYNLL1 limits nucleolytic degradation of DNA ends by associating with the DNA end-resection machinery (MRN complex, BLM helicase and DNA2 endonuclease). In vitro, DYNLL1 binds directly to MRE11 to limit its end-resection activity. Therefore, we infer that DYNLL1 is an important anti-resection factor that influences genomic stability and responses to DNA-damaging chemotherapy.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • BRCA1 Protein / deficiency*
  • BRCA1 Protein / genetics
  • CRISPR-Cas Systems / genetics
  • Cell Line, Tumor
  • Chromosome Aberrations
  • Cytoplasmic Dyneins / metabolism*
  • DNA / metabolism*
  • DNA Damage / drug effects
  • Drug Resistance, Neoplasm / drug effects
  • Female
  • Gene Editing
  • Genes, BRCA1*
  • Genomic Instability / drug effects
  • Homologous Recombination / drug effects
  • Humans
  • MRE11 Homologue Protein / metabolism*
  • Mutation
  • Ovarian Neoplasms / genetics
  • Ovarian Neoplasms / pathology
  • Platinum / pharmacology
  • Poly(ADP-ribose) Polymerase Inhibitors / pharmacology
  • Protein Binding
  • Recombinational DNA Repair* / drug effects
  • Transcription Factors / metabolism


  • ATMIN protein, human
  • BRCA1 Protein
  • BRCA1 protein, human
  • MRE11 protein, human
  • Poly(ADP-ribose) Polymerase Inhibitors
  • Transcription Factors
  • Platinum
  • DNA
  • MRE11 Homologue Protein
  • DYNLL1 protein, human
  • Cytoplasmic Dyneins