Keratin　17　(K17)　is　a　cytoskeletal　protein　that　is　part　of　the　intermediate　filaments　in　epidermal　keratinocytes.　In　K17−/−　mice,　ionizing　radiation　induced　more　severe　hair　follicle　damage,　whereas　the　epidermal　inflammatory　response　was　attenuated　compared　with　that　in　wild-type　mice.　Both　p53　and　K17　have　a　major　impact　on　global　gene　expression　because　over　70%　of　the　differentially　expressed　genes　in　the　skin　of　wild-type　mice　showed　no　expression　change　in　p53−/−　or　K17−/−　skin　after　ionizing　radiation.　K17　does　not　interfere　with　the　dynamics　of　p53　activation;　rather,　global　p53　binding　in　the　genome　is　altered　in　K17−/−　mice.　The　absence　of　K17　leads　to　aberrant　cell　cycle　progression　and　mitotic　catastrophe　in　epidermal　keratinocytes,　which　is　due　to　nuclear　retention,　thus　reducing　the　degradation　of　B-Myb,　a　key　regulator　of　the　G2/M　cell　cycle　transition.　These　results　expand　our　understanding　of　the　role　of　K17　in　regulating　global　gene　expression　and　ionizing　radiation–induced　skin　damage.　©　2023