title: Differential roles for Chk1 and FANCD2 in ATR-mediated signalling for psoralen photoactivation-induced senescence.
abstract: Cellular senescence is a stress-inducible, naturally irreversible cell cycle arrest, which is likely linked with ageing. Premature ageing of the skin is a prominent side effect of psoralen photoactivation, which is used for the treatment of various skin disorders. Previously, we have shown that DNA interstrand crosslink formation by photoactivated psoralens induces a senescent phenotype in primary fibroblasts that is mediated by Ataxia telangiectasia-mutated and Rad3-related (ATR) kinase. Checkpoint kinase 1 (Chk1) initiates cell cycle checkpoints, and FANCD2 is known to be involved in DNA damage-induced S-phase arrest and crosslink repair. In this study, we examined a role for Chk1 and FANCD2 as downstream effectors of ATR in senescence signalling. We demonstrate that Chk1 and FANCD2 are long-lastingly activated after psoralen photoactivation. Separate and combined reduction in Chk1 and FANCD2 expression by small interfering RNA (siRNA) preceding irradiation partly prevented the initiation of the senescence-like phenotype, whereas siRNA (Chk1 and FANCD2) transfection of senesced fibroblasts released cells from growth arrest. We observed that Chk1 and FANCD2 signal equally and additively for senescence induction, while Chk1 is predominantly responsible for maintaining persistent cell cycle arrest. In conclusion, Chk1 and FANCD2 function downstream of ATR in a non-redundant manner for the establishment and maintenance of psoralen photoactivation-induced senescence.
authors: Department of Dermatology, University of Cologne, Cologne, Germany.
authors: Miriam G
authors: MG
authors: Hovest
authors: Thomas
authors: T
authors: Krieg
authors: Gernot
authors: G
authors: Herrmann
mesh_terms: D064007:Ataxia Telangiectasia Mutated Proteins; D018797:Cell Cycle Proteins / Q000378:metabolism*; D002478:Cells, Cultured; D016922:Cellular Senescence / Q000187:drug effects / Q000502:physiology; D000071877:Checkpoint Kinase 1; D004249:DNA Damage; D052236:Fanconi Anemia Complementation Group D2 Protein / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D011564:Furocoumarins / Q000009:adverse effects; D006801:Humans; D011701:PUVA Therapy / Q000009:adverse effects; D011494:Protein Kinases / Q000235:genetics / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000235:genetics; D015398:Signal Transduction; D015595:Skin Aging / Q000187:drug effects / Q000235:genetics / Q000502:physiology*
chemical_list: D018797:Cell Cycle Proteins; C499905:FANCD2 protein, human; D052236:Fanconi Anemia Complementation Group D2 Protein; D011564:Furocoumarins; D034741:RNA, Small Interfering; D011494:Protein Kinases; C576597:ATR protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; C000605867:CHEK1 protein, human; D000071877:Checkpoint Kinase 1; D017346:Protein Serine-Threonine Kinases