STIM1 nuclear functiona role in DNA damage response

Abstract

This Doctoral Thesis has focused on the study of an additional and non-canonical function for the Ca2+ sensor STIM1, specifically, the study of its nuclear function. To establish this objective, we rely on the results of the STIM1 interactome, in which we observed interaction with numerous nucleo-cytoplasmic transport proteins, as well as proteins of the FA/BRCA pathway, involved in DNA damage repair. In this work we have shown that STIM1 presents a nuclear localization sequence that allows it to be transported to the nucleus and that this translocation is increased after exposure to mitomycin-C (MMC), a DNA interstrand crosslinking agent. In addition, it has been shown that STIM1-deficient cells show DNA damage, increased sensitivity to MMC and cell cycle arrest in the G2/M phase. Likewise, it is shown that the absence of STIM1 leads to replicative stress, which is responsible for endogenous DNA damage. Additionally, in this study we have shown that STIM1 interacts with the nuclear chromatin and that both the transport of STIM1 to the nucleus and its interaction with chromatin are necessary to prevent DNA damage. Finally, this work shows that STIM1 normalizes nuclear FANCD2 protein levels, so that the absence of STIM1 is associated with lower levels of nuclear FANCD2, which would explain the higher sensitivity of STIM1-KO cells to MMC.