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Defects in the posttranscriptional modifications of mitochondrial tRNAs have been linked to human diseases, but their pathophysiology remains elusive. In this report, we investigated the molecular mechanism underlying a deafness-associated tRNAIle 4295A>G mutation affecting a highly conserved adenosine at position 37, 3′ adjacent to the tRNA’s anticodon. Primer extension and methylation activity assays revealed that the m.4295A>G mutation introduced a tRNA methyltransferase 5 (TRMT5)-catalyzed m1G37 modification of tRNAIle. Molecular dynamics simulations suggested that the m.4295A>G mutation affected tRNAIle structure and function, supported by increased melting temperature, conformational changes and instability of mutated tRNA. An in vitro processing experiment revealed that the m.4295A>G mutation reduced the 5′ end processing efficiency of tRNAIle precursors, catalyzed by RNase P. We demonstrated that cybrid cell lines carrying the m.4295A>G mutation exhibited significant alterations in aminoacylation and steady-state levels of tRNAIle. The aberrant tRNA metabolism resulted in the impairment of mitochondrial translation, respiratory deficiency, decreasing membrane potentials and ATP production, increasing production of reactive oxygen species and promoting autophagy. These demonstrated the pleiotropic effects of m.4295A>G mutation on tRNAIle and mitochondrial functions. Our findings highlighted the essential role of deficient posttranscriptional modifications in the structure and function of tRNA and their pathogenic consequence of deafness.

In this report, we investigated the molecular mechanism underlying a deafness-associated m.7516delA mutation affecting the 5′ end processing sites of mitochondrial tRNAAsp and tRNASer(UCN). An in vitro processing experiment demonstrated that m.7516delA mutation caused the aberrant 5′ end processing of tRNASer(UCN) and tRNAAsp precursors, catalyzed by RNase P. Using cytoplasmic hybrids (cybrids) derived from one hearing-impaired Chinese family bearing the m.7516delA mutation and control, we demonstrated the asymmetrical effects of m.7516delA mutation on the processing of tRNAs in the heavy (H)-strand and light (L)-strand polycistronic transcripts. Specially, the m.7516delA mutation caused the decreased levels of tRNASer(UCN) and downstream five tRNAs, including tRNATyr from the L-strand transcripts and tRNAAsp from the H-strand transcripts. Strikingly, mutant cybrids exhibited the lower level of COX2 mRNA and accumulation of longer and uncleaved precursors of COX2 from the H-strand transcripts. Aberrant RNA metabolisms yielded variable reductions in the mitochondrial proteins, especially marked reductions in the levels of ND4, ND5, CO1, CO2 and CO3. The impairment of mitochondrial translation caused the proteostasis stress and respiratory deficiency, diminished ATP production and membrane potential, increased production of reactive oxygen species and promoted apoptosis. Our findings provide new insights into the pathophysiology of deafness arising from mitochondrial tRNA processing defects.

Somatic mutations of the chromatin remodeling gene ARID2 are observed in ∼7% of human lung adenocarcinomas (LUADs). However, the role of ARID2 in the pathogenesis of LUADs remains largely unknown. Here we find that ARID2 expression is decreased during the malignant progression of both human and mice LUADs. Using two KrasG12D-based genetically engineered murine models, we demonstrate that ARID2 knockout significantly promotes lung cancer malignant progression and shortens overall survival. Consistently, ARID2 knockdown significantly promotes cell proliferation in human and mice lung cancer cells. Through integrative analyses of ChIP-Seq and RNA-Seq data, we find that Hspa1a is up-regulated by Arid2 loss. Knockdown of Hspa1a specifically inhibits malignant progression of Arid2-deficient but not Arid2-wt lung cancers in both cell lines as well as animal models. Treatment with an HSPA1A inhibitor could significantly inhibit the malignant progression of lung cancer with ARID2 deficiency. Together, our findings establish ARID2 as an important tumor suppressor in LUADs with novel mechanistic insights, and further identify HSPA1A as a potential therapeutic target in ARID2-deficient LUADs.

Aim: To conduct the clinical, genetic, and molecular characterization of 494 Han Chinese subjects with tic disorders (TD). Methods: In the present study, we performed the mutational analysis of 22 mitochondrial tRNA genes in a large cohort of 494 Han Chinese subjects with TD via Sanger sequencing. These variants were then assessed for their pathogenic potential via phylogenetic, functional, and structural analyses. Results: A total of 73 tRNA gene variants (49 known and 24 novel) on 22 tRNA genes were identified. Among these, 18 tRNA variants that were absent or present in Limitations: The phenotypic variability and incomplete penetrance of tic disorders in pedigrees carrying these tRNA mutations suggested the involvement of modifier factors, such as nuclear encoded genes associated mitochondrion, mitochondrial haplotypes, epigenetic, and environmental factors. Conclusion: Our data provide the evidence that mitochondrial tRNA mutations are the important causes of tic disorders among Chinese population. These findings also advance current understanding regarding the clinical relevance of tRNA mutations, and will guide future studies aimed at elucidating the pathophysiology of maternal tic disorders.

Background Alternative splicing (AS) is important in the regulation of gene expression and aberrant AS is emerging as a major factor in the pathogenesis of human conditions, including cancer. Triple-negative breast cancer (TNBC) is the most challenging subtype of breast cancer with strong invasion, high rate of metastasis, and poor prognosis. Here we report a systematic profiling of aberrant AS in TNBC. Methods The percent spliced in (PSI) values for AS events in 151 TNBC patients were obtained from The Cancer Genome Atlas (TCGA) SpliceSeq database. Univariate Cox and stepwise Multivariate Cox regression analyses were conducted to find the best prognostic AS model. Splicing regulatory networks were constructed by prognosis-related spliceosome and aberrant AS events. Additionally, pathway enrichment and gene set enrichment analysis (GSEA) were further employed to reveal the significant pathways for prognosis-related AS genes. Finally, splicing regulatory networks were constructed via Spearman's rank correlation coefficients between prognosis-related AS events and splicing factor expressions. Results A total of 1,397 prognosis-associated AS events were identified in TNBC. The majority of the parent genes of prognostic AS events exhibited direct interactions to each other in the STRING gene network. Pathways of focal adhesion (p < 0.001), RNA splicing (p = 0.007), homologous recombination (p = 0.042) and ECM-receptor interaction (p = 0.046) were found to be significantly enriched for prognosis-related AS. Additionally, the area under curve (AUC) of the best AS prognostic predictor model reached 0.949, showing a powerful capability to predict outcomes. The Exon Skip (ES) type of AS events displayed more robust and efficient capacity in predicting performance than any other specific AS events type in terms of prognosis. The ES AS signature might confer a strong oncogenic phenotype in the high-risk group with elevated activities in cell cycle and SUMOylating pathways of tumorigenesis, while programmed cell death and metabolism pathways were found to be enriched in the low-risk group of TNBC. The splicing correlation network also revealed a regulatory mode of prognostic splicing factors (SFs) in TNBC. Conclusion Our analysis of AS events in TNBC could not only contribute to elucidating the tumorigenesis mechanism of AS but also provide clues to uncovering underlying prognostic biomarkers and therapeutic targets for further study.

Leber's hereditary optic neuropathy (LHON) is a maternal inheritance of eye disease because of the mitochondrial DNA (mtDNA) mutations. We previously discovered a 3866T>C mutation within the gene for the ND1 subunit of complex I as possibly amplifying disease progression for patients bearing the disease-causing 11778G>A mutation within the gene for the ND4 subunit of complex I. However, whether and how the ND1 mutation exacerbates the ND4 mutation were unknown. In this report, we showed that four Chinese families bearing both m.3866T>C and m.11778G>A mutations exhibited higher penetrances of LHON than 6 Chinese pedigrees carrying only the m.3866T>C mutation or families harboring only the m.11778G>A mutation. The protein structure analysis revealed that the m.3866T>C (I187T) and m.11778G>A (R340H) mutations destabilized the specific interactions with other residues of ND1 and ND4, thereby altering the structure and function of complex I. Cellular data obtained using cybrids, constructed by transferring mitochondria from the Chinese families into mtDNA-less (ρ°) cells, demonstrated that the mutations perturbed the stability, assembly, and activity of complex I, leading to changes in mitochondrial ATP levels and membrane potential and increasing the production of reactive oxygen species. These mitochondrial dysfunctions promoted the apoptotic sensitivity of cells and decreased mitophagy. Cybrids bearing only the m.3866T>C mutation displayed mild mitochondrial dysfunctions, whereas those harboring both m.3866T>C and m.11778G>A mutations exhibited greater mitochondrial dysfunctions. These suggested that the m.3866T>C mutation acted in synergy with the m.11778G>A mutation, aggravating mitochondrial dysfunctions and contributing to higher penetrance of LHON in these families carrying both mtDNA mutations.

A Chinese family with matrilineally inherited obesity was assessed and its clinical, genetic, and molecular profiling was conducted. Obesity was observed in matrilineal relatives (3 out of 7) of a single generation (of 3 alive generations) in this family. On pedigree analysis and sequencing of their mitochondrial DNA (mtDNA), a novel homoplasmic mutation of the mitochondrial tRNACys gene (5802A>G) was identified in these individuals. This mutation correlated with a destabilized conserved base pair in this tRNA anticodon stem. Position 30 is known to be crucial for carrying out effective codon recognition and stability of tRNA. In accordance with the importance of this conserved site, we observed that the predicted structure of tRNACys with the mutation was noticeably remodeled in a molecular dynamics simulation when compared with the isoform of the wild-type. All other 46 mutations observed in the individual’s mtDNA were known variants belonging to haplogroup D4. Thus, this is the first report that provides evidence of the association between a mutation in tRNA and an enhanced risk of maternally transmissible obesity, offering more insights into obesity and its underlying nature.

The 1555A→G mutation in mitochondrial 12S rRNA has been associated with aminoglycoside-induced and non-syndromic deafness in many individuals worldwide. Mitochondrial genetic modifiers are proposed to influence the phenotypic expression of m.1555A→G mutation. Here, we report that a deafness-susceptibility allele (m.4317A→G) in the tRNAIle gene modulates the phenotype expression of m.1555A→G mutation. Strikingly, a large Han Chinese pedigree carrying both m.4317A→G and m.1555A→G mutations exhibited much higher penetrance of deafness than those carrying only the m.1555A→G mutation. The m.4317A→G mutation affected a highly conserved adenine at position 59 in the T-loop of tRNAIle. We therefore hypothesized that the m.4317A→G mutation alters both structure and function of tRNAIle. Using lymphoblastoid cell lines derived from members of Chinese families (three carrying both m.1555A→G and m.4317A→G mutations, three harboring only m.1555A→G mutation, and three controls lacking these mutations), we found that the cell lines bearing both m.4317A→G and m.1555A→G mutations exhibited more severe mitochondrial dysfunctions than those carrying only the m.1555A→G mutation. We also found that the m.4317A→G mutation perturbed the conformation, stability, and aminoacylation efficiency of tRNAIle. These m.4317A→G mutation-induced alterations in tRNAIle structure and function aggravated the defective mitochondrial translation and respiratory phenotypes associated with the m.1555A→G mutation. Furthermore, mutant cell lines bearing both m.4317A→G and m.1555A→G mutations exhibited greater reductions in the mitochondrial ATP levels and membrane potentials and increasing production of reactive oxygen species than those carrying only the m.1555A→G mutation. Our findings provide new insights into the pathophysiology of maternally inherited deafness arising from the synergy between mitochondrial 12S rRNA and tRNA mutations.

Ferulic acid (FA), a hydroxycinnamic acid, is an organic compound found in several plant species. Previous studies have shown that FA contains anti-inflammatory and anti-arthritic properties. This study aimed to investigate the anti-arthritic activity and possible mechanism(s) of action of FA in complete Freund’s adjuvant (CFA)-induced arthritis. The progression of rheumatoid arthritis (RA) involves the activation of the Janus kinase-signal transducer and activator of transcription (JAK/STAT) pathway by proinflammatory cytokines. Molecular docking of FA showed promising Janus kinase 2 (JAK2) inhibition with a docking score of − 6.7, which is comparable with that of ruxolitinib, a standard inhibitor. However, in vitro JAK2 inhibition assay showed a half maximal inhibitory concentration (IC50) of 6.67 ± 0.88 µg/ml. Both doses of FA (25 and 50 mg/kg) significantly attenuated primary (volume of paw edema) and secondary lesions. CFA-induced arthritic rats showed a significant decrease in body weight, A/G ratio, and Hb but showed a greater arthritic index, ESR levels, and percentage of lymphocytes. These alterations were significantly reduced in rats treated with FA and prednisolone. FA also reversed changes to biochemical parameters and inflammatory markers, such as C-reactive protein (CRP) and rhematoid factor (RF). Additionally, we found CFA-induced arthritis triggered the secretion of TNF- α, increased JAK2 levels, and reduced TGF-β levels in tissue homogenates. However, in rats treated with FA, such alterations significantly improved. Thus, our results reveal that FA contains anti-arthritic activity, which is possibly mediated by the inhibition of the JAK/STAT pathway.

Mutations in the mitochondrial tRNAs have been reported to be the important cause of hearing loss. However, only a few cases have been identified thus far and the prevalence of mitochondrial tRNA mutations in hearing-impaired patients remain unclear. Here we performed the mutational analysis of 22 mitochondrial tRNA genes in a large cohort of 887 Han Chinese subjects with hearing loss by Sanger sequencing. The systemic evaluation of putative pathogenic variants was further carried out by frequency in controls (

Mitochondria maintain a distinct pool of ribosomal machinery, including tRNAs and tRNAs activating enzymes, such as mitochondrial tyrosyl-tRNA synthetase (YARS2). Mutations in YARS2, which typically lead to the impairment of mitochondrial protein synthesis, have been linked to an array of human diseases including optic neuropathy. However, the lack of YARS2 mutation animal model makes us difficult to elucidate the pathophysiology underlying YARS2 deficiency. To explore this system, we generated YARS2 knockout (KO) HeLa cells and zebrafish using CRISPR/Cas9 technology. We observed the aberrant tRNATyr aminoacylation overall and reductions in the levels in mitochondrion- and nucleus-encoding subunits of oxidative phosphorylation system (OXPHOS), which were especially pronounced effects in the subunits of complex I and complex IV. These deficiencies manifested the decreased levels of intact supercomplexes overall. Immunoprecipitation assays showed that YARS2 bound to specific subunits of complex I and complex IV, suggesting the posttranslational stabilization of OXPHOS. Furthermore, YARS2 ablation caused defects in the stability and activities of OXPHOS complexes. These biochemical defects could be rescued by the overexpression of YARS2 cDNA in the YARS2KO cells. In zebrafish, the yars2KO larva conferred deficient COX activities in the retina, abnormal mitochondrial morphology, and numbers in the photoreceptor and retinal ganglion cells. The zebrafish further exhibited the retinal defects affecting both rods and cones. Vision defects in yars2KO zebrafish recapitulated the clinical phenotypes in the optic neuropathy patients carrying the YARS2 mutations. Our findings highlighted the critical role of YARS2 in the stability and activity of OXPHOS and its pathological consequence in vision impairments.

Mitochondrial DNA (mtDNA) mutations have been associated with Leber’s hereditary optic neuropathy (LHON) and their pathophysiology remains poorly understood. In this study, we investigated the pathophysiology of a LHON susceptibility allele (m.3394T>C, p.30Y>H) in the Mitochondrial (MT)-ND1 gene. The incidence of m.3394T>C mutation was 2.7% in the cohort of 1741 probands with LHON. Extremely low penetrances of LHON were observed in 26 pedigrees carrying only m.3394T>C mutation, while 21 families bearing m.3394T>C, together with m.11778G>A or m.14484T>C mutation, exhibited higher penetrance of LHON than those in families carrying single mtDNA mutation(s). The m.3394T>C mutation disrupted the specific electrostatic interactions between Y30 of p.MT-ND1 with the sidechain of E4 and backbone carbonyl group of M1 of NDUFA1 (NADH dehydrogenase [ubiquinone] 1 alpha subcomplex subunit 1) of complex I, thereby altering the structure and function of complex I. We demonstrated that these cybrids bearing only m.3394T>C mutation caused mild mitochondrial dysfunctions and those harboring both m.3394T>C and m.11778G>A mutations exhibited greater mitochondrial dysfunctions than cybrids carrying only m.11778G>A mutation. In particular, the m.3394T>C mutation altered the stability of p.MT-ND1 and complex I assembly. Furthermore, the m.3394T>C mutation decreased the activities of mitochondrial complexes I, diminished mitochondrial ATP levels and membrane potential and increased the production of reactive oxygen species in the cybrids. These m.3394T>C mutation-induced alterations aggravated mitochondrial dysfunctions associated with the m.11778G>A mutation. These resultant biochemical defects contributed to higher penetrance of LHON in these families carrying both mtDNA mutations. Our findings provide new insights into the pathophysiology of LHON arising from the synergy between mitochondrial ND1 and ND4 mutations.

Abnormal activation of neddylation modification and dysregulated energy metabolism are frequently seen in many types of cancer cells. Whether and how neddylation modification affects cellular metabolism remains largely unknown. Here, we showed that MLN4924, a small-molecule inhibitor of neddylation modification, induces mitochondrial fission-to-fusion conversion in breast cancer cells via inhibiting ubiquitylation and degradation of fusion-promoting protein mitofusin 1 (MFN1) by SCF(β-TrCP) E3 ligase and blocking the mitochondrial translocation of fusion-inhibiting protein DRP1. Importantly, MLN4924-induced mitochondrial fusion is independent of cell cycle progression, but confers cellular survival. Mass-spectrometry-based metabolic profiling and mitochondrial functional assays reveal that MLN4924 inhibits the TCA cycle but promotes mitochondrial OXPHOS. MLN4924 also increases glycolysis by activating PKM2 via promoting its tetramerization. Biologically, MLN4924 coupled with the OXPHOS inhibitor metformin, or the glycolysis inhibitor shikonin, significantly inhibits cancer cell growth both in vitro and in vivo. Together, our study links neddylation modification and energy metabolism, and provides sound strategies for effective combined cancer therapies.

Background aims The engraftment of mesenchymal stem cells (MSCs) is reported to promote recovery of renal function in animal models of acute kidney injury (AKI). However, it is unknown whether mesenchymal-like progenitors (MPs) derived from human embryonic stem cells (hESCs) can mediate similar therapeutic effects. We investigated the responses of recipient renal tissue to engraftment of hESC-MPs and underlying mechanisms of these effects. Methods We measured blood urea nitrogen and creatinine levels of AKI mice with hESC-MPs transplantation and control mice. We performed renal morphology analysis by immunohistochemistry and electron microscopy to confirm the renoprotective effects of engrafted hESC-MPs. Proliferation, apoptosis and gene expression of tubular cells were also monitored by immunohistochemistry and real-time quantitative polymerase chain reaction to investigate the mechanisms that occurred. Results After transplantation of hESC-MPs into mice with cisplatin-induced AKI, improvements in renal function and recovery from tubular epithelial cell injury were observed. Engrafted hESC-MPs were localized to areas of injured kidney 5 days after cisplatin induction, where they promoted tubular cell proliferation and decreased kidney cell apoptosis. The beneficial effect was further confirmed by the capability of the engrafted cells to up-regulate renal gene expression of anti-inflammatory cytokines and pro-survival cytokines. Meanwhile, infusion of these cells reduced renal gene expression of pro-inflammatory cytokines and monocyte chemotactic protein-1, a chemokine that stimulates monocyte and macrophage infiltration. Conclusions Our results show that infused hESC-MPs may promote recovery from AKI by regulating related cytokines.

Recombination activating gene 1/2 endonuclease (RAG) initiates V(D)J recombination in developing B and T lymphocytes via “on-target” activity at bona fide recombination signal sequences (RSSs) to generate diverse antibodies. “Off-target” RAG activity is thought to be rare, but can cause oncogenic interstitial deletions or chromosomal translocations that contribute to immature B and T lymphocyte cancers. Given that potential RAG off-target sites occur frequently in the genome, it has been a mystery how this potentially dangerous activity is suppressed. We generated mice with a pair of bona fide V(D)J RSSs (“V(D)J cassette”) in the first intron of c-myc on mouse chromosome 15. When introduced into an ATM-deficient background, the c-myc V(D)J cassette-containing mice recurrently develop B cell lymphomas with oncogenic c-myc translocations/amplifications involving the Igh locus on chromosome 12. These amplifications are generated by breakage-fusion-bridge (“BFB”) cycles from dicentric (15;12) chromosomes formed through fusion of RAG-generated Igh double-stranded breaks (DSBs) to sequences downstream of c-myc. Notably, the translocations downstream of c-myc occurred exclusively on V(D)J cassette-containing alleles, but did not involve the cassette. Based on this finding, we proposed that the V(D)J cassette mediates DSBs downstream of c-myc by activating RAG cutting at linked cryptic RSSs. We developed a linear amplification-mediated (“LAM”) version of our high-throughput genome-wide translocation sequencing approach (“LAM-HTGTS”) to robustly identify “prey” endogenous DNA DSBs that join to introduced or endogenous “bait” DSBs. We used LAM-HTGTS to reveal genome-wide DSBs that joined to RAG-generated bait DSBs. We found that translocations between RAG-induced DSBs in the c-myc V(D)J cassette to Igh occur only in the absence of ATM. Strikingly, however, we discovered a large number of deletions from the c-myc cassette to sequences just upstream of c-myc (1 kb) and up to 1.7 Mb downstream of c-myc in WT and ATM-deficient cells. Moreover, insertion of a pair of bona fide RSSs into 12 random sites genome-wide induced large numbers of RAG-initiated DSBs leading to cassette involved deletions and inversions spreading upstream and downstream of a given cassette from 200 kb to over 2 Mb, respectively. In each case, regions of RAG off-target activity fell into a well-defined topologically associated domain (TAD) into which the cassette integrated. Such domains generally were flanked by convergent CTCF binding sites (CBEs), such as those our lab implicated in Igh locus V(D)J recombination control, but sometimes also involved sub-domains of a CTCF-defined TAD. We showed these TAD-associated DSBs to enrich at “cryptic RSSs” determined by conserved “CAC” motifs. We also captured these DSBs via LAM-HTGTS from Cas9/gRNA DSBs within a TAD and proved them to be RAG-generated. We found dramatic changes of on-target profiles and expansion of off-target RAG-generated Igh locus DSBs when CBEs acting as boundary of DH-JH recombination domain were deleted. Based on these overall findings, we propose that antigen receptor loci exploit fixed CBE-based TADs to restrict RAG activity within them, but also evolved “regulated” sub-domains to further focus and re-focus RAG activity developmentally. We also used LAM-HTGTS to identify 89 RAG off-targets that participate in chromosomal translocations and show RAG off-targets occur in pairs in highly accessible regions such as enhancers and promoters within a TAD. Beyond providing a mechanisms for the generation of recurrent B cell lymphomas in ATM-deficient mice with a V(D)J cassette in c-myc, our findings help explain the origin of certain recurrent interstitial deletions and translocations in tumors that arise from human developing lymphocytes. Citation Format: Jiazhi Hu, Yu Zhang, Lijuan Zhao, Richard Frock, Zhou Du, Robin M. Meyers, Feilong Meng, David G. Schatz, Frederick W. Alt. Topologically associated domains genome-wide restrict the off-target activity of recombination activating gene 1/2 endonuclease. [abstract]. In: Proceedings of the CRI-CIMT-EATI-AACR Inaugural International Cancer Immunotherapy Conference: Translating Science into Survival; September 16-19, 2015; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(1 Suppl):Abstract nr A180.

Activation-induced cytidine deaminase (AID) plays a critical role in human immune system. It initiates both somatic hypermutation (SHM) and class switch recombination (CSR) of immunoglobulin (Ig) genes and possibly performs destructive mutations on non-Ig genes, related in cancer generation and development. Due to the aggregation behavior and extremely low activity of AID protein in vitro, the molecular basis of its function is still unclear. Using protein engineer approach, we successfully produced fully functional monomeric human AID mutants with dramatically elevated activity in vitro and intact CSR ability in vivo. Biochemistry data showed structured DNA with single strands joint feature, like G-quadruplex or partially branched DNA, can provide 10-20 fold AID affinity and 50-100 fold deaminase activity, suggests such structure can perform as direct AID recruiters in vivo. AID self-assembly upon DNA binding was observed and likely to be important for CSR. Stable AID-DNA complexes were purified in constant stoichiometry. Using crystallography method, we solved structures of AID alone and in complex with different DNA components in atomic resolution. Analyze on substrate binding interface and potential self-oligomerization interface together with abundant assay results support a structure based AID targeting and processing model during CSR and potential AID recruiting mechanism in causing off-target mutations. For the first time, our study reveals a closer look at this mystery protein, and provides solid basis for further investigation in AID function in antibody production and related diseases. Citation Format: Qi Qiao, Li Wang, Feilong Meng, Hao Wu. Mechanistic elucidation of activation-induced deaminase (AID) in immunity and cancer. [abstract]. In: Proceedings of the CRI-CIMT-EATI-AACR Inaugural International Cancer Immunotherapy Conference: Translating Science into Survival; September 16-19, 2015; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(1 Suppl):Abstract nr A174.