Repair of 2'-C-cyano-2'-deoxy-1-beta-D-arabino-pentofuranosylcytosine-induced DNA single-strand breaks by transcription-coupled nucleotide excision repair.
The cytosine nucleoside analogue 2'-C-cyano-2'-deoxy-1-beta-d-arabino-pentofuranosylcytosine (CNDAC) causes DNA single-strand breaks after its incorporation into DNA. This investigation sought to determine if DNA excision repair pathways were activated to repair this damage. Neither the base excision repair nor the mismatch repair pathway seemed to be involved. Cells deficient in the CSB protein, which initiates transcription-coupled nucleotide excision repair (NER) pathway (TC-NER), exhibited increased clonogenic sensitivity to CNDAC, whereas cells deficient in XPC, which initiates global genome NER, were slightly resistant relative to wild-type cells. The cells lacking either helicase XPB, which unwinds 5' of the lesion, or endonuclease XPF, which incises 5' to a lesion, exhibited increased clonogenic sensitivity to CNDAC, as did cells lacking the XPF partner protein ERCC1. This sensitization was independent of p53 function. Repletion of XPF restored sensitivity comparable with the wild type. In contrast, cells lacking either XPD, the 3'-helicase, or the 3'-endonuclease XPG were equally as sensitive as wild-type cells. In comparison, cells deficient in XPF were not sensitized to other cytosine nucleoside analogues, troxacitabine and cytarabine. Thus, the single-strand nick caused by CNDAC is recognized and, in part, repaired by the TC-NER pathway. NER proteins that function in the 5' direction relative to the UV-induced lesion also participate in the repair of the CNDAC-induced nick, in contrast to proteins that process on the 3' side of the lesion.
Wang
Yaqing
Y
Department of Experimental Therapeutics, The University of Texas M. D. Anderson Cancer Center, Houston, Texas, USA.
Liu
Xiaojun
X
Matsuda
Akira
A
Plunkett
William
W
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D016466:CHO Cells; D045744:Cell Line, Tumor; D006224:Cricetinae; D003412:Cricetulus; D003561:Cytarabine / Q000031:analogs & derivatives* / Q000494:pharmacology; D003596:Cytosine / Q000031:analogs & derivatives / Q000737:chemistry / Q000494:pharmacology; D004249:DNA Damage; D004260:DNA Repair; D004148:Dioxolanes / Q000494:pharmacology; D006367:HeLa Cells; D006801:Humans; D051379:Mice; D014158:Transcription, Genetic; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
D000970:Antineoplastic Agents; D004148:Dioxolanes; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D003561:Cytarabine; C070279:2'-cyano-2'-deoxyarabinofuranosylcytosine; C074908:troxacitabine; D003596:Cytosine