Opposing Roles of FANCJ and HLTF Protect Forks and Restrain Replication during Stress

Cell Rep. 2018 Sep 18;24(12):3251-3261. doi: 10.1016/j.celrep.2018.08.065.


The DNA helicase FANCJ is mutated in hereditary breast and ovarian cancer and Fanconi anemia (FA). Nevertheless, how loss of FANCJ translates to disease pathogenesis remains unclear. We addressed this question by analyzing proteins associated with replication forks in cells with or without FANCJ. We demonstrate that FANCJ-knockout (FANCJ-KO) cells have alterations in the replisome that are consistent with enhanced replication stress, including an aberrant accumulation of the fork remodeling factor helicase-like transcription factor (HLTF). Correspondingly, HLTF contributes to fork degradation in FANCJ-KO cells. Unexpectedly, the unrestrained DNA synthesis that characterizes HLTF-deficient cells is FANCJ dependent and correlates with S1 nuclease sensitivity and fork degradation. These results suggest that FANCJ and HLTF promote replication fork integrity, in part by counteracting each other to keep fork remodeling and elongation in check. Indicating one protein compensates for loss of the other, loss of both HLTF and FANCJ causes a more severe replication stress response.

Keywords: DNA replication; FANCJ/BACH1/BRIP1; Fanconi anemia; fork degradation; fork protection; helicase; hereditary breast cancer; iPOND; replication stress response; replisome.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • DNA Damage
  • DNA Replication*
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism*
  • Fanconi Anemia Complementation Group Proteins / genetics
  • Fanconi Anemia Complementation Group Proteins / metabolism*
  • HCT116 Cells
  • HEK293 Cells
  • Humans
  • RNA Helicases / genetics
  • RNA Helicases / metabolism*
  • Transcription Factors / genetics
  • Transcription Factors / metabolism*


  • DNA-Binding Proteins
  • Fanconi Anemia Complementation Group Proteins
  • HLTF protein, human
  • Transcription Factors
  • BRIP1 protein, human
  • RNA Helicases