Transcriptional repressor ZBTB1 promotes chromatin remodeling and translesion DNA synthesis

Mol Cell. 2014 Apr 10;54(1):107-118. doi: 10.1016/j.molcel.2014.02.017. Epub 2014 Mar 20.


Timely DNA replication across damaged DNA is critical for maintaining genomic integrity. Translesion DNA synthesis (TLS) allows bypass of DNA lesions using error-prone TLS polymerases. The E3 ligase RAD18 is necessary for proliferating cell nuclear antigen (PCNA) monoubiquitination and TLS polymerase recruitment; however, the regulatory steps upstream of RAD18 activation are less understood. Here, we show that the UBZ4 domain-containing transcriptional repressor ZBTB1 is a critical upstream regulator of TLS. The UBZ4 motif is required for PCNA monoubiquitination and survival after UV damage. ZBTB1 associates with KAP-1, a transcriptional repressor whose phosphorylation relaxes chromatin after DNA damage. ZBTB1 depletion impairs formation of phospho-KAP-1 at UV damage sites and reduces RAD18 recruitment. Furthermore, phosphorylation of KAP-1 is necessary for efficient PCNA modification. We propose that ZBTB1 is required for localizing phospho-KAP-1 to chromatin and enhancing RAD18 accessibility. Collectively, our study implicates a ubiquitin-binding protein in orchestrating chromatin remodeling during DNA repair.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Binding Sites
  • Cell Nucleus / drug effects
  • Cell Nucleus / metabolism*
  • Cell Nucleus / radiation effects
  • Cell Survival
  • Chickens
  • Chromatin Assembly and Disassembly*
  • DNA / biosynthesis*
  • DNA Damage*
  • DNA Replication*
  • DNA-Binding Proteins / metabolism
  • DNA-Directed DNA Polymerase / metabolism
  • Enzyme Inhibitors / pharmacology
  • HEK293 Cells
  • HeLa Cells
  • Humans
  • Nucleic Acid Synthesis Inhibitors
  • Phosphorylation
  • Proliferating Cell Nuclear Antigen / metabolism
  • RNA Interference
  • Repressor Proteins / genetics
  • Repressor Proteins / metabolism*
  • Signal Transduction
  • Time Factors
  • Transfection
  • Tripartite Motif-Containing Protein 28
  • Ubiquitin-Protein Ligases
  • Ubiquitination
  • Ultraviolet Rays


  • DNA-Binding Proteins
  • Enzyme Inhibitors
  • Nucleic Acid Synthesis Inhibitors
  • Proliferating Cell Nuclear Antigen
  • RAD18 protein, human
  • Repressor Proteins
  • ZBTB1 protein, human
  • DNA
  • TRIM28 protein, human
  • Tripartite Motif-Containing Protein 28
  • Ubiquitin-Protein Ligases
  • DNA-Directed DNA Polymerase
  • Rad30 protein