The IRES‐Mediated Translation of Cytoplasmic Serine Hydroxymethyltransferase (cSHMT) is Stimulated by UV‐Induced DNA Damage

Abstract

Cytoplasmic serine hydroxymethyltransferase (cSHMT) is a key regulator of folate‐mediated one‐carbon metabolism. By preferentially directing one‐carbon units to thymidylate synthase (TS), cSHMT gives purine synthesis priority over methionine synthesis, resulting in elevated levels of thymidylate for DNA replication and repair. The 5′ untranslated region (UTR) of the cSHMT transcript contains an internal ribosome entry site (IRES) that regulates cSHMT expression through interactions with the IRES trans‐acting factors BrunoL2 and heavy chain ferritin (HCF). In this study, we investigate the physiological function of the cSHMT IRES. We show that cSHMT IRES activity is stimulated in response to a non‐lethal dose of UV irradiation, resulting in a four‐fold increase in cSHMT protein levels despite a global inhibition of cap‐dependent translation. Furthermore, we show that the mechanism of IRES stimulation involves the UV‐induced activation of HCF transcription and the relocalization of BrunoL2 to the cytoplasm. This response appears to be specific to DNA damage‐induced cellular stress, as nocodazole‐induced cell cycle arrest does not produce the same results. The UV‐induced increase in cSHMT expression is accompanied by an increase in the nuclear localization of cSHMT and TS, suggesting that cSHMT IRES activity functions to provide thymidylate for the repair of DNA lesions arising from UV irradiation.