Human HLTF functions as a ubiquitin ligase for proliferating cell nuclear antigen polyubiquitination

Proc Natl Acad Sci U S A. 2008 Mar 11;105(10):3768-73. doi: 10.1073/pnas.0800563105. Epub 2008 Mar 3.


Human helicase-like transcription factor (HLTF) is frequently inactivated in colorectal and gastric cancers. Here, we show that HLTF is a functional homologue of yeast Rad5 that promotes error-free replication through DNA lesions. HLTF and Rad5 share the same unique structural features, including a RING domain embedded within a SWI/SNF helicase domain and an HIRAN domain. We find that inactivation of HLTF renders human cells sensitive to UV and other DNA-damaging agents and that HLTF complements the UV sensitivity of a rad5Delta yeast strain. Also, similar to Rad5, HLTF physically interacts with the Rad6-Rad18 and Mms2-Ubc13 ubiquitin-conjugating enzyme complexes and promotes the Lys-63-linked polyubiquitination of proliferating cell nuclear antigen at its Lys-164 residue. A requirement of HLTF for error-free postreplication repair of damaged DNA is in keeping with its cancer-suppression role.

Publication types

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

MeSH terms

  • Adenosine Triphosphatases / metabolism
  • Cell Line
  • DNA Helicases
  • DNA-Binding Proteins / metabolism*
  • Drug Resistance / drug effects
  • Drug Resistance / radiation effects
  • Genetic Complementation Test
  • Humans
  • Ligases / metabolism
  • Lysine / metabolism
  • Methyl Methanesulfonate / pharmacology
  • Mutation / genetics
  • Polyubiquitin / metabolism*
  • Proliferating Cell Nuclear Antigen / metabolism*
  • Protein Binding / drug effects
  • Protein Binding / radiation effects
  • Saccharomyces cerevisiae / drug effects
  • Saccharomyces cerevisiae / metabolism
  • Saccharomyces cerevisiae / radiation effects
  • Saccharomyces cerevisiae Proteins / metabolism
  • Transcription Factors / metabolism*
  • Ubiquitin-Conjugating Enzymes / metabolism
  • Ubiquitin-Protein Ligases / metabolism*
  • Ubiquitination* / drug effects
  • Ubiquitination* / radiation effects
  • Ultraviolet Rays


  • DNA-Binding Proteins
  • HLTF protein, human
  • Proliferating Cell Nuclear Antigen
  • RAD18 protein, human
  • Saccharomyces cerevisiae Proteins
  • Transcription Factors
  • Polyubiquitin
  • Methyl Methanesulfonate
  • UBE2N protein, human
  • UBE2V2 protein, human
  • Ubiquitin-Conjugating Enzymes
  • Ubiquitin-Protein Ligases
  • Adenosine Triphosphatases
  • RAD5 protein, S cerevisiae
  • DNA Helicases
  • Ligases
  • Lysine