AIMP3 depletion causes genome instability and loss of stemness in mouse embryonic stem cells

Abstract

Aminoacyl-tRNA synthetase-interacting multifunctional protein-3 (AIMP3) is a component of the multi-aminoacyl-tRNA synthetase complex and is involved in diverse cellular processes. Given that AIMP3 deficiency causes early embryonic lethality in mice, AIMP3 is expected to play a critical role in early mouse development. To elucidate a functional role of AIMP3 in early mouse development, we induced AIMP3 depletion in mouse embryonic stem cells (mESCs) derived from blastocysts of AIMP3f/f; CreERT2 mice. In the present study, AIMP3 depletion resulted in loss of self-renewal and ability to differentiate to three germ layers in mESCs. AIMP3 depletion led to accumulation of DNA damage by blocking double-strand break repair, in particular homologous recombination. Through microarray analysis, the p53 signaling pathway was identified as being activated in AIMP3-depleted mESCs. Knockdown of p53 rescued loss of stem cell characteristics by AIMP3 depletion in mESCs. These results imply that AIMP3 depletion in mESCs leads to accumulation of DNA damage and p53 transactivation, resulting in loss of stemness. We propose that AIMP3 is involved in maintenance of genome stability and stemness in mESCs.

Evolution of the multi-tRNA synthetase complex and its role in cancer

“…AIMP2 is one of three nonenzymatic factors, and it works as a potent tumor suppressor through multiple pathways, including TGF-␤- (36), TNF␣-(37), Wnt- (38), and p53 (39)-mediated pathways. AIMP3 is mobilized to the nucleus by DNA damage (46,47) or via an oncogenic stimulus (21) to activate p53 via ATM/ATR for DNA repair. B, MRS forms a complex with AIMP3 via their GST-homology domains (17).…”

“…Deletion of AIMP3 both in embryonic and adult stages induces severe and lethal DNA damage (46,47), suggesting the vital role of AIMP3 for maintaining the integrity of cellular DNA. AIMP3 is normally tightly bound to the N-terminal GSThomology domain of MRS via its similar domain and serves as a conduit for the passage of the methionine-charged tRNA to the initiation complex, as mentioned earlier (Fig.…”

“…Among the various DNA repair mechanisms, we focused on the homologous recombination (HR)-based DNA repair pathway because it included the largest number of the ARS interactors. AIMP3 was shown to facilitate DNA repair through homologous DNA recombination (46,47), although its additional role in nonhomologous DNA recombination is not excluded. The network model revealed four instances in which MSC-ARSs/AIMPs interact with core molecules in the HRbased DNA repair pathway (Fig.…”

HIF1α‐mediated AIMP3 suppression delays stem cell aging via the induction of autophagy

“…In response to DNA damage, AIMP3 can dissociate from the MSC and translocate to the nucleus for DNA repair and induce ATM/ATR‐p53‐mediated cell cycle arrest (Park et al, ). Recently, the induced depletion of AIMP3 was reported to cause severe DNA damage and to show a phenocopy of acute radiation syndrome in adult mice (Kim, Kim et al, ), leading to embryonic stem cell death with increased DNA damage (Kim, Jeon, Kim, & Jang, ). All of these findings support the functional significance of AIMP3 for DNA integrity.…”

EEF1E1 (eukaryotic translation elongation factor 1 epsilon 1)

“…A great number of mutations in the genomic sequence and in the amino acid sequence for EEF1E1 were discovered in cancer cells that are obviously genetically more unstable respect normal ones. However, depletion of EEF1E1 causes itself genomic instability in cells (Kim et al, 2018) and makes the cells susceptible to transformation by single oncogenes (Park et al, 2006). The genomic alterations observed include also the formation of novel fusion genes.…”