Abstract
Multiple myeloma (MM) is a hematologic malignancy characterized by high genomic instability. Here we provide evidence that hyper-activation of DNA ligase III (LIG3) is crucial for genomic instability and survival of MM cells. LIG3 mRNA expression in MM patients correlates with shorter survival and even increases with more advanced stage of disease. Knockdown of LIG3 impairs MM cells viability in vitro and in vivo, suggesting that neoplastic plasmacells are dependent on LIG3-driven repair. To investigate the mechanisms involved in LIG3 expression, we investigated the post-transcriptional regulation. We identified miR-22-3p as effective negative regulator of LIG3 in MM. Enforced expression of miR-22 in MM cells downregulated LIG3 protein, which in turn increased DNA damage inhibiting in vitro and in vivo cell growth. Taken together, our findings demonstrate that myeloma cells are addicted to LIG3, which can be effectively inhibited by miR-22, promoting a novel axis of genome stability regulation.
Highlights
Hallmarks of cancer are produced by progressive genomic aberrations that confer selective growth advantage to cancer cells [1]
We investigated the potential involvement of DNA ligases in the genomic instability and survival of MM cells
By comparing prognostic relevance of DNA ligases mRNA expression through whole gene expression data set analyses, we found that high LIG3 mRNA levels were significantly correlated to worse outcome in MM patients and increased during progression of disease and in relapsed patients
Summary
Hallmarks of cancer are produced by progressive genomic aberrations that confer selective growth advantage to cancer cells [1]. LIG1 gene encodes DNA ligase I (LigI), which predominantly operates in DNA replication [8], with minor role in excision repair process (BER and NER), and alternative non homologous end joining (Alt-NHEJ) repair. LIG4 gene encodes DNA ligase IV (LigIV), which catalyzes the last step of canonical-NHEJ repair pathway [9]. Alternative translation initiation generates two different isoform of DNA ligase IIIα (LigIIIα) [10]: (a) nuclear LigIIIα, predominantly involved in excision repair process and Alt-NHEJ repair [11]; (b) mitochondrial LigIIIα, which is the DNA ligase involved in mitochondrial genome replication and repair [12]. A germ cell-specific alternative splicing mechanism of LIG3 generates DNA ligase III β (LigIIIβ), which has been hypothesized to be involved in meiotic recombination and/ or DNA repair in haploid sperm [13]
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