RB·E2F1 complex mediates DNA damage responses through transcriptional regulation of ZBRK1.
RB plays an essential role in DNA damage-induced growth arrest and regulates the expression of several factors essential for DNA repair machinery. However, how RB coordinates DNA damage response through transcriptional regulation of genes involved in growth arrest remains largely unexplored. We examined whether RB can mediate the response to DNA damage through modulation of ZBRK1, a zinc finger-containing transcriptional repressor that can modulate the expression of GADD45A, a DNA damage response gene, to induce cell cycle arrest in response to DNA damage. We found that the ZBRK1 promoter contains an authentic E2F-recognition sequence that specifically binds E2F1, but not E2F4 or E2F6, together with chromatin remodeling proteins CtIP and CtBP to form a repression complex that suppresses ZBRK1 transcription. Furthermore, loss of RB-mediated transcriptional repression led to an increase in ZBRK1 transcript levels, correlating with increased sensitivity to ultraviolet (UV) and methyl methanesulfonate-induced DNA damage. Taken together, these results suggest that the RB·CtIP (CtBP interacting protein)/CtBP (C terminus-binding protein) /E2F1 complex plays a critical role in ZBRK1 transcriptional repression, and loss of this repression may contribute to cellular sensitivity of DNA damage, ultimately leading to carcinogenesis.
Liao
Ching-Chun
CC
From the Institute of Basic Medical Sciences, Tainan, Taiwan.
Tsai
Connie Y
CY
Department of Biological Chemistry, University of California, Irvine, California 92697.
Chang
Wen-Chang
WC
Institute of Pharmacology, College of Medicine, Tainan, Taiwan; Center for Gene Regulation and Signal Transduction Research, National Cheng Kung University, Tainan, Taiwan.
Lee
Wen-Hwa
WH
Department of Biological Chemistry, University of California, Irvine, California 92697. Electronic address: whlee@uci.edu.
Wang
Ju-Ming
JM
Center for Gene Regulation and Signal Transduction Research, National Cheng Kung University, Tainan, Taiwan; Institute of Biosignal Transduction, Tainan, Taiwan. Electronic address: yumingw@mail.ncku.edu.tw.
D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects / Q000502:physiology / Q000528:radiation effects; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D042002:Chromatin Assembly and Disassembly / Q000187:drug effects / Q000502:physiology / Q000528:radiation effects; D004249:DNA Damage / Q000187:drug effects / Q000502:physiology* / Q000528:radiation effects; D050687:E2F1 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D004706:Endodeoxyribonucleases; D006801:Humans; D008698:Mesylates / Q000494:pharmacology; D046912:Multiprotein Complexes / Q000235:genetics / Q000378:metabolism*; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D012097:Repressor Proteins / Q000096:biosynthesis* / Q000235:genetics; D020218:Response Elements / Q000502:physiology*; D016160:Retinoblastoma Protein / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D014466:Ultraviolet Rays / Q000009:adverse effects; D000097642:GADD45 Proteins
D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D050687:E2F1 Transcription Factor; D004706:Endodeoxyribonucleases; D008698:Mesylates; D046912:Multiprotein Complexes; D009687:Nuclear Proteins; D012097:Repressor Proteins; D016160:Retinoblastoma Protein; C493753:E2F1 protein, human; C439070:GADD45A protein, human; D000097642:GADD45 Proteins; C422407:ZNF350 protein, human; C045880:methanesulfonic acid; C410741:RBBP8 protein, human