CHIP-mediated degradation and DNA damage-dependent stabilization regulate base excision repair proteins.
Base excision repair (BER) is the major pathway for processing of simple lesions in DNA, including single-strand breaks, base damage, and base loss. The scaffold protein XRCC1, DNA polymerase beta, and DNA ligase IIIalpha play pivotal roles in BER. Although all these enzymes are essential for development, their cellular levels must be tightly regulated because increased amounts of BER enzymes lead to elevated mutagenesis and genetic instability and are frequently found in cancer cells. Here we report that BER enzyme levels are linked to and controlled by the level of DNA lesions. We demonstrate that stability of BER enzymes increases after formation of a repair complex on damaged DNA and that proteins not involved in a repair complex are ubiquitylated by the E3 ubiquitin ligase CHIP and subsequently rapidly degraded. These data identify a molecular mechanism controlling cellular levels of BER enzymes and correspondingly the efficiency and capacity of BER.
Parsons
Jason L
JL
Medical Research Council Radiation Oncology and Biology Unit, University of Oxford, Oxfordshire OX1 3QU, UK.
Tait
Phillip S
PS
Finch
David
D
Dianova
Irina I
II
Allinson
Sarah L
SL
Dianov
Grigory L
GL
D000595:Amino Acid Sequence; D000818:Animals; D002843:Chromatin / Q000378:metabolism; D004249:DNA Damage; D000072481:DNA Ligase ATP; D011088:DNA Ligases / Q000235:genetics / Q000378:metabolism*; D019951:DNA Polymerase beta / Q000235:genetics / Q000378:metabolism*; D004260:DNA Repair; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D006367:HeLa Cells; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism; D046911:Macromolecular Substances / Q000378:metabolism; D018832:Molecular Chaperones / Q000378:metabolism; D008969:Molecular Sequence Data; D016877:Oxidants / Q000378:metabolism; D000075223:Poly-ADP-Ribose Binding Proteins; D011499:Protein Processing, Post-Translational; D025801:Ubiquitin / Q000235:genetics / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism*; D000076105:X-ray Repair Cross Complementing Protein 1; D029867:Xenopus Proteins
D002843:Chromatin; D004268:DNA-Binding Proteins; D046911:Macromolecular Substances; D018832:Molecular Chaperones; D016877:Oxidants; D000075223:Poly-ADP-Ribose Binding Proteins; D025801:Ubiquitin; D000076105:X-ray Repair Cross Complementing Protein 1; C000619371:XRCC1 protein, human; D029867:Xenopus Proteins; D006861:Hydrogen Peroxide; C467728:STUB1 protein, human; D044767:Ubiquitin-Protein Ligases; D019951:DNA Polymerase beta; D011088:DNA Ligases; D000072481:DNA Ligase ATP; C000618816:DNA ligase III alpha protein, Xenopus