1111

CHEK1

checkpoint kinase 1;CHEK1;checkpoint kinase 1

CHK1 checkpoint homolog|Checkpoint, S. pombe, homolog of, 1|Chk1-S|cell cycle checkpoint kinase|checkpoint kinase-1|serine/threonine-protein kinase Chk1

11q24.2

protein-coding

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.