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Differential roles for Chk1 and FANCD2 in ATR‐mediated signalling for psoralen photoactivation‐induced senescence
Author(s) -
Hovest Miriam G.,
Krieg Thomas,
Herrmann Gernot
Publication year - 2011
Publication title -
experimental dermatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.108
H-Index - 96
eISSN - 1600-0625
pISSN - 0906-6705
DOI - 10.1111/j.1600-0625.2011.01365.x
Subject(s) - senescence , dna damage , fancd2 , microbiology and biotechnology , chek1 , biology , cell cycle checkpoint , dna repair , cell cycle , small interfering rna , telomere , transfection , chemistry , cell , cell culture , dna , fanconi anemia , biochemistry , genetics
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.