Distinct functions for WRN and TP53 in a shared pathway of cellular response to 1-beta-D-arabinofuranosylcytosine and bleomycin.
Mutations in the WRN or the TP53 genes lead to spontaneous genetic instability, an elevated risk of tumor formation, and sensitivity to compounds that interfere with DNA replication, such as camptothecin and DNA interstrand cross-linking drugs. We investigated the hypothesis that WRN and TP53 are involved in cellular responses to DNA replication-blocking lesions by exposing WRN deficient and TP53 mutant lymphoblastoid cell lines (LCLs) to 1-beta-d-arabinofuranosylcytosine (AraC) and bleomycin. Loss of WRN or TP53 function resulted in induction of apoptosis and lesser proliferative survival in response to AraC and bleomycin. WRN and TP53 operate in a shared DNA damage response pathway, since in cells in which TP53 was inactivated by SV-40 transformation, no difference in AraC and bleomycin sensitivity was found regardless of WRN status. In contrast to TP53 mutant LCLs, WRN-deficient cells showed unaffected cell cycle arrest after AraC and bleomycin exposure, which indicates that WRN is not involved in DNA damage-activated cell cycle arrest. Neither WRN nor TP53 deficiency affected cellular recovery from exposure to AraC and bleomycin, which disagrees with a direct role in repair of these DNA lesions. Our results indicate that WRN and TP53 perform different functions in a shared DNA damage response pathway.
Poot
Martin
M
Department of Pathology, University of Washington, Seattle, WA 98195-7705, USA. mpoot@u.washington.edu
Jin
Xiaoyang
X
Hill
Juliane P
JP
Gollahon
Katherine A
KA
Rabinovitch
Peter S
PS
D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology*; D017209:Apoptosis; D001761:Bleomycin / Q000494:pharmacology; D002461:Cell Line, Transformed; D002470:Cell Survival; D002478:Cells, Cultured; D003561:Cytarabine / Q000494:pharmacology; D004249:DNA Damage / Q000187:drug effects / Q000502:physiology; D004265:DNA Helicases / Q000172:deficiency / Q000502:physiology*; D005090:Exodeoxyribonucleases; D005192:Family Health; D006801:Humans; D008214:Lymphocytes / Q000473:pathology; D009154:Mutation; D053484:RecQ Helicases; D015398:Signal Transduction / Q000187:drug effects*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000502:physiology*; D014898:Werner Syndrome / Q000188:drug therapy / Q000473:pathology*; D000071657:Werner Syndrome Helicase
D000964:Antimetabolites, Antineoplastic; D016159:Tumor Suppressor Protein p53; D003561:Cytarabine; D001761:Bleomycin; D005090:Exodeoxyribonucleases; D004265:DNA Helicases; D053484:RecQ Helicases; C098785:WRN protein, human; D000071657:Werner Syndrome Helicase