Human HLTF mediates postreplication repair by its HIRAN domain-dependent replication fork remodelling

Nucleic Acids Res. 2015 Dec 2;43(21):10277-91. doi: 10.1093/nar/gkv896. Epub 2015 Sep 8.


Defects in the ability to respond properly to an unrepaired DNA lesion blocking replication promote genomic instability and cancer. Human HLTF, implicated in error-free replication of damaged DNA and tumour suppression, exhibits a HIRAN domain, a RING domain, and a SWI/SNF domain facilitating DNA-binding, PCNA-polyubiquitin-ligase, and dsDNA-translocase activities, respectively. Here, we investigate the mechanism of HLTF action with emphasis on its HIRAN domain. We found that in cells HLTF promotes the filling-in of gaps left opposite damaged DNA during replication, and this postreplication repair function depends on its HIRAN domain. Our biochemical assays show that HIRAN domain mutant HLTF proteins retain their ubiquitin ligase, ATPase and dsDNA translocase activities but are impaired in binding to a model replication fork. These data and our structural study indicate that the HIRAN domain recruits HLTF to a stalled replication fork, and it also provides the direction for the movement of the dsDNA translocase motor domain for fork reversal. In more general terms, we suggest functional similarities between the HIRAN, the OB, the HARP2, and other domains found in certain motor proteins, which may explain why only a subset of DNA translocases can carry out fork reversal.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine Triphosphatases / metabolism
  • Cell Line
  • DNA / metabolism
  • DNA Repair*
  • DNA Replication*
  • DNA-Binding Proteins / chemistry*
  • DNA-Binding Proteins / metabolism
  • Humans
  • Proliferating Cell Nuclear Antigen / metabolism
  • Protein Structure, Tertiary
  • Transcription Factors / chemistry*
  • Transcription Factors / metabolism
  • Ubiquitin-Protein Ligases / metabolism


  • DNA-Binding Proteins
  • HLTF protein, human
  • Proliferating Cell Nuclear Antigen
  • Transcription Factors
  • DNA
  • Ubiquitin-Protein Ligases
  • Adenosine Triphosphatases