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Inhibition of cyclin-dependent kinase activity exacerbates H202-induced DNA damage in Kindler syndrome keratinocytes

Research output: Contribution to journalArticle

Original languageEnglish
JournalExperimental Dermatology
Early online date1 Jul 2019
DOIs
Publication statusE-pub ahead of print - 1 Jul 2019

Abstract

Kindler Syndrome (KS) is an autosomal recessive skin disorder characterized by skin blistering and photosensitivity. KS is caused by loss of function mutations in FERMT1, which encodes Kindlin‐1. Kindlin‐1 is a FERM domain containing adaptor protein that is found predominantly at cell‐extracellular matrix adhesions where it binds to integrin β subunits and is required for efficient integrin activation. Using keratinocytes derived from a patient with KS, into which wild type Kindlin‐1 (Kin1WT) has been expressed, we show that Kindlin‐1 binds to cyclin‐dependent kinase (CDK)1 and CDK2. CDK1 and CDK2 are key regulators of cell cycle progression, however, cell cycle analysis showed only small differences between the KS and KS‐Kin1WT keratinocytes. In contrast, G2/M cell cycle arrest in response to oxidative stress induced by hydrogen peroxide (H2O2) was enhanced in KS keratinocytes but not KS‐Kin1WT cells, following inhibition of CDK activity. Furthermore, KS keratinocytes were more sensitive to DNA damage in response to H2O2 and this was exacerbated by treatment with the CDK inhibitor roscovitine. Thus, in Kindlin‐1 deficient keratinocytes, CDK activity can further regulate oxidative damage induced cell cycle arrest and DNA damage. This provides further insight into the key pathways that control sensitivity to oxidative stress in KS patients.

    Research areas

  • CDK1, CDK2, Kindlin-1, cell cycle, DNA damage

ID: 97161335