Cyclins and CDKS
Counter-intuitively, cyclin-CDK complexes, normally involved in cell cycle progression, are actually stabilized upon DNA damage. Rather than promote proliferation, in this context, these complexes assist in establishing cytostasis.
Response to UVB
ATM/ATR phosphorylate E2F1 on ser31 (ser29 in mouse) to promote association with TopBP1, and subsequent recruitment to regions of DNA damage containing CPD photoproduct in DNA. Here, E2F1 promotes repair by recruiting the GCN5 HAT to induce H3K9 acetylation to increase accessibility to DNA repair machinery.
In keratinocytes treated with UVB, cyclin A2 and Cyclin E are stabilized in an E2F1-dependent manner. This stabilization is required for cell cycle arrest.
Exposure of cells to mitomycin C or UV irradiation, but not ionizing radiation, induces stabilization of cyclin E. Stabilization of cyclin E reduces the activity of Cdk2-cyclin A, resulting in a slowing of S phase progression and arrest. In addition, cyclin E is shown to be required for stabilization of Cdc6, which is required for activation of Chk1 and the replication checkpoint pathway. Furthermore, the stabilization of cyclin E in response to replication fork barriers depends on ATR, but not Nbs1 or Chk1. These results indicate that in addition to its well studied role in promoting cell cycle progression, cyclin E also has a role in regulating cell cycle arrest in response to DNA damage.
Counter-intuitively, cyclin-CDK complexes, normally involved in cell cycle progression, are actually stabilized upon DNA damage. Rather than promote proliferation, in this context, these complexes assist in establishing cytostasis.
Response to UVB
ATM/ATR phosphorylate E2F1 on ser31 (ser29 in mouse) to promote association with TopBP1, and subsequent recruitment to regions of DNA damage containing CPD photoproduct in DNA. Here, E2F1 promotes repair by recruiting the GCN5 HAT to induce H3K9 acetylation to increase accessibility to DNA repair machinery.
In keratinocytes treated with UVB, cyclin A2 and Cyclin E are stabilized in an E2F1-dependent manner. This stabilization is required for cell cycle arrest.
Exposure of cells to mitomycin C or UV irradiation, but not ionizing radiation, induces stabilization of cyclin E. Stabilization of cyclin E reduces the activity of Cdk2-cyclin A, resulting in a slowing of S phase progression and arrest. In addition, cyclin E is shown to be required for stabilization of Cdc6, which is required for activation of Chk1 and the replication checkpoint pathway. Furthermore, the stabilization of cyclin E in response to replication fork barriers depends on ATR, but not Nbs1 or Chk1. These results indicate that in addition to its well studied role in promoting cell cycle progression, cyclin E also has a role in regulating cell cycle arrest in response to DNA damage.