A kinase-independent function of c-Abl in promoting proteolytic destruction of damaged DNA binding proteins

Mol Cell. 2006 May 19;22(4):489-99. doi: 10.1016/j.molcel.2006.04.021.


Damaged DNA binding proteins (DDBs) play a critical role in the initial recognition of UV-damaged DNA and mediate recruitment of nucleotide excision repair factors. Previous studies identified DDB2 as a target of the CUL-4A ubiquitin ligase. However, the biochemical mechanism governing DDB proteolysis and its underlying physiological function in the removal of UV-induced DNA damage are largely unknown. Here, we report that the c-Abl nonreceptor tyrosine kinase negatively regulates the repair of UV-induced photolesions on genomic DNA. Biochemical studies revealed that c-Abl promotes CUL-4A-mediated DDB ubiquitination and degradation in a manner that does not require its tyrosine kinase activity both under normal growth conditions and following UV irradiation. Moreover, c-Abl activates DDB degradation in part by alleviating the inhibitory effect of CAND1/TIP120A on CUL-4A. These results revealed a kinase-independent function of c-Abl in a ubiquitin-proteolytic pathway that regulates the damage recognition step of nucleotide excision repair.

Publication types

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

MeSH terms

  • Animals
  • Cells, Cultured
  • Cullin Proteins / metabolism
  • DNA Damage*
  • DNA Repair / physiology*
  • DNA-Binding Proteins / deficiency
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism*
  • Gene Silencing
  • Mice
  • Proto-Oncogene Proteins c-abl / deficiency
  • Proto-Oncogene Proteins c-abl / genetics
  • Proto-Oncogene Proteins c-abl / metabolism*
  • RNA, Small Interfering / genetics
  • Transcription Factors / genetics
  • Transcription Factors / metabolism
  • Ubiquitin / metabolism
  • Ultraviolet Rays / adverse effects


  • Cul4a protein, mouse
  • Cullin Proteins
  • DNA-Binding Proteins
  • Ddb2 protein, mouse
  • RNA, Small Interfering
  • Transcription Factors
  • Ubiquitin
  • Proto-Oncogene Proteins c-abl