title: A gain-of-function senescence bypass screen identifies the homeobox transcription factor DLX2 as a regulator of ATM-p53 signaling.
abstract: Senescence stimuli activate multiple tumor suppressor pathways to initiate cycle arrest and a differentiation program characteristic of senescent cells. We performed a two-stage, gain-of-function screen to select for the genes whose enhanced expression can bypass replicative senescence. We uncovered multiple genes known to be involved in p53 and Rb regulation and ATM regulation, two components of the CST (CTC1-STN1-TEN1) complex involved in preventing telomere erosion, and genes such as REST and FOXO4 that have been implicated in aging. Among the new genes now implicated in senescence, we identified DLX2, a homeobox transcription factor that has been shown to be required for tumor growth and metastasis and is associated with poor cancer prognosis. Growth analysis showed that DLX2 expression led to increased cellular replicative life span. Our data suggest that DLX2 expression reduces the protein components of the TTI1/TTI2/TEL2 complex, a key complex required for the proper folding and stabilization of ATM and other members of the PIKK (phosphatidylinositol 3-kinase-related kinase) family kinase, leading to reduced ATM-p53 signaling and senescence bypass. We also found that the overexpression of DLX2 exhibited a mutually exclusive relationship with p53 alterations in cancer patients. Our functional screen identified novel players that may promote tumorigenesis by regulating the ATM-p53 pathway and senescence.
authors.affiliation: Department of Genetics, Harvard University Medical School, Howard Hughes Medical Institute, Division of Genetics, Brigham and Women's Hospital, Boston, Massachusetts 02115 USA.
authors.forename: Yifan
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Genetics, Harvard University Medical School, Howard Hughes Medical Institute, Division of Genetics, Brigham and Women's Hospital, Boston, Massachusetts 02115 USA.
authors.forename: Qikai
authors.initials: Q
authors.lastname: Xu
authors.affiliation: Department of Genetics, Harvard University Medical School, Howard Hughes Medical Institute, Division of Genetics, Brigham and Women's Hospital, Boston, Massachusetts 02115 USA.
authors.forename: Laura
authors.initials: L
authors.lastname: Sack
authors.affiliation: Department of Genetics, Harvard University Medical School, Howard Hughes Medical Institute, Division of Genetics, Brigham and Women's Hospital, Boston, Massachusetts 02115 USA.
authors.forename: Chanhee
authors.initials: C
authors.lastname: Kang
authors.affiliation: Department of Genetics, Harvard University Medical School, Howard Hughes Medical Institute, Division of Genetics, Brigham and Women's Hospital, Boston, Massachusetts 02115 USA.
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Elledge
mesh_terms: D064007:Ataxia Telangiectasia Mutated Proteins / Q000378:metabolism*; D002460:Cell Line; D016922:Cellular Senescence / Q000235:genetics; D019295:Computational Biology; D005786:Gene Expression Regulation / Q000235:genetics; D018398:Homeodomain Proteins / Q000235:genetics* / Q000378:metabolism*; D006801:Humans; D015203:Reproducibility of Results; D015398:Signal Transduction / Q000235:genetics*; D059505:Telomere Homeostasis / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism*; D015533:Transcriptional Activation / Q000235:genetics; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
chemical_list: C088334:Distal-less homeobox proteins; D018398:Homeodomain Proteins; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins
keywords: ATM; genetic screen; senescence
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