eIF3a Regulation of NHEJ Repair Protein Synthesis and Cellular Response to Ionizing Radiation

Abstract

Translation initiation in protein synthesis regulated by eukaryotic initiation factors (eIFs) is a crucial step in controlling gene expression. eIF3a has been shown to regulate protein synthesis and cellular response to treatments by anticancer agents including cisplatin by regulating nucleotide excision repair. In this study, we tested the hypothesis that eIF3a regulates the synthesis of proteins important for the repair of double-strand DNA breaks induced by ionizing radiation (IR). We found that eIF3a upregulation sensitized cellular response to IR while its downregulation caused resistance to IR. eIF3a increases IR-induced DNA damages and decreases non-homologous end joining (NHEJ) activity by suppressing the synthesis of NHEJ repair proteins. Furthermore, analysis of existing patient database shows that eIF3a expression associates with better overall survival of breast, gastric, lung, and ovarian cancer patients. These findings together suggest that eIF3a plays an important role in cellular response to DNA-damaging treatments by regulating the synthesis of DNA repair proteins and, thus, eIIF3a likely contributes to the outcome of cancer patients treated with DNA-damaging strategies including IR.

eIF3a regulation of mTOR signaling and translational control via HuR in cellular response to DNA damage

“…Although mTORC2 is known to phosphorylate Akt at Ser 473 43 , we did not find any effect of eIF3a knockdown on the expression of Rictor (unpublished observation), a key component of mTORC2 44 . Although this finding does not rule out the possible involvement of mTORC2 in mediating eIF3a regulation of Akt, it has been shown previously that eIF3a suppresses the synthesis of DNA-PKcs 7 , 8 , which is known to activate and phosphorylate Akt 45 , 46 . Thus, it is tempting to speculate that DNA-PKcs may mediate eIF3a regulation of Akt phosphorylation and activation.…”

“…The biological significances of eIF3a in cancer disease have also been recognized, including tumorigenesis 3 and prognosis 4 . eIF3a has been shown to cause cellular sensitivity to DNA-damaging treatments including cisplatin 5 , 6 , doxorubicin 5 , 7 and ionizing radiation 8 , which may contribute to tumorigenesis and prognosis. These observations have been ascribed to the non-canonical function of eIF3a in suppressing synthesis of DNA repair proteins important for nucleotide excision repair (NER) of DNA crosslink adducts induced by cisplatin 5 , 6 and for non-homologous end joining (NHEJ) repair of double strand DNA breaks induced by doxorubicin and radiation 7 , 8 .…”

The Downregulation of eIF3a Contributes to Vemurafenib Resistance in Melanoma by Activating ERK via PPP2R1B

“…As a key regulator in cancer, eIF3a is expressed at high levels in multiple cancers and is relevant to the sensitivity of DNA damage-induced therapy, such as platinum agents and ionizing radiation (Tumia et al, 2020). As shown in our previous study, eIF3a increases the sensitivity of ovarian cancer and non-small cell lung cancer to platinum-based chemotherapy, and the patients with a high level of eIF3a have a better prognosis (Yin et al, 2011b;.…”

“…Previous studies, including our own study, supported the hypothesis that eIF3a knockdown reduces the cellular response to cisplatin by regulating the expression of DNA repair proteins in lung cancer (Yin et al, 2011a), nasopharyngeal carcinoma (Liu et al, 2011), and ovarian cancer . Tumia R et al also reported that high eIF3a expression increases radiotherapy and chemotherapy responses in patients with breast, gastric, lung, and ovarian cancer (Tumia et al, 2020), further suggesting that eIF3a may affect patient responses to treatments.…”

Translation initiation factor eIF3a regulates glucose metabolism and cell proliferation via promoting small GTPase Rheb synthesis and AMPK activation

“…It has also been shown to associate with cancer prognosis and patient response to chemotherapy ( 11 , 12 , 13 ) and to regulate cancer cell proliferation ( 14 , 15 , 16 , 17 ). Although the eIF3a function in cancer prognosis has been shown to attribute to its function in suppressing synthesis of DNA damage repair proteins in cellular response to DNA-damaging drugs and radiation ( 11 , 18 , 19 ), it remains to be determined how eIF3a controls cancer cell proliferation.…”