Figure 2.

Cellular responses to hypoxia: Under oxic conditions PHD2 adds hydroxyl groups to HIF1α. This facilitates E3-dependent ubiquitination (not shown) and subsequent proteasomal degradation. Hypoxia inhibits PHD2-mediated hydroxylation, allowing HIF1α to dimerise with HIF1β, translocate to the nucleus and mediate transcription of target genes. Hypoxia also induces the unfolded protein response. Under hypoxia the ER has reduced capacity to mediate protein maturation. The ER chaperone BiP binds misfolded proteins in the ER and releases the luminal domain of PERK, facilitating PERK auto-phosphorylation and activation. Subsequent phosphorylation of eIF2α attenuates its role in global translation initiation and leads to activation of the ATF4 transcription factor. Collectively, these hypoxic responses can suppress transcription and translation of components of multiple DNA repair pathways, including HR, MMR and BER. BER, base excision repair; eIF2α, eukaryotic initiation factor 2α; ER, endoplasmic reticulum; HIF1α, hypoxia inducible factor 1α; HR, homologous recombination; MMR, mismatch repair; PERK, PKR-like ER kinase; PHD2, proline hydroxylase D2.