{"doi":"10.1002/ctm2.1400","title":"The roles and therapeutic implications of messenger RNA internal <i>N</i><sup>7</sup>‐methylguanosine and <i>N</i><sup>6</sup>‐methyladenosine modifications in chemoresistance","abstract":"Resistance to chemotherapy is responsible for the death of most cancer patients. RNA modifications are key players in post-transcriptional gene regulation and their dysregulations contribute to tumor initiation, progression, and resistance to chemotherapy. Despite the identification of over 170 chemical modifications in nearly all types of RNAs, the biological functions and underlying mechanisms of the vast majority of RNA modifications remain elusive in the context of tumorigenesis and drug resistance. N6-methyladenosine (m6A) is the most prevalent internal modification in eukaryotic messenger RNAs (mRNAs). The characterization of proteins that deposit, remove, and recognize mRNA m6A marks, as writers, erasers and readers, respectively, has revealed the profound roles of m6A in determining mRNA fates during both physiological and pathological processes. Besides m6A, another commonly observed positively charged modification is N7-methylguanosine (m7G), which is ubiquitously located at the 5′ cap of mRNAs. This m7G cap is fundamental to mRNA stability, export, and translation. Meanwhile, multiple independent studies have revealed that m7G modification could also be introduced internally onto mRNAs by the METTL1/WDR4 methyltransferase complex.1, 2 In eukaryotic cells, the internal m7G/G ratio in mRNAs ranges from 0.02% to 0.05%, roughly at 5%−10% of the level of mRNA m6A/A ratio. However, unlike m6A, the functions of mRNA internal m7G remain largely unexplored. As the role of internal m7G is mediated by its reader proteins, identification of such readers is pivotal for us to understand the function of internal m7G. Our recent work discovered the Quaking (QKI) protein (including three isoforms, QKI5, QKI6 and QKI7) as the first reader for internal m7G modification.3 Utilizing multiple high-throughput sequencing approaches, we demonstrated that QKI7 regulates the stability and translation efficiency of a subset of internal m7G-modified transcripts under stress conditions, rendering cancer cells more responsive to chemotherapy drugs in vitro and in vivo. Tumours are complex ecosystems that dynamically adapt to various types of external stress stimuli. Evidence is emerging that RNA modifications serve as critical regulatory mechanisms in cancer cells to respond to external stress, including chemotherapeutics, and are critical for tumorigenesis and drug resistance. Consistently, the expression of their regulators (i.e., writers, erasers, and readers) is frequently dysregulated in tumours. Notably, many genes involved in drug resistance are decorated with m6A on their transcripts, including drug-metabolizing enzymes (e.g. CYP2C8), multidrug efflux transporters (e.g., ABCG2, ABCC9 and ABCC10), and DNA damage repair genes (e.g. p53, BRCA1).4 Additionally, a recent transcriptome-wide profiling study of internal m7G revealed a significantly lower internal m7G level on ABC transporter-encoded transcripts (key players in multidrug resistance) in drug-resistant acute myeloid leukaemia (AML) cells than in regular AML cells.5 Therefore, targeting the dysregulated m6A/m7G machinery appears to be a promising strategy to overcome cancer chemoresistance (Figure 1). Stress conditions including chemotherapy drugs induce the formation of stress granules (SGs), the membraneless cytoplasmic ribonucleoprotein particles in cells. The formation of SGs requires certain RNA binding proteins such as G3BP1 to act as a molecular hub to trigger SG assembly.6 Current evidence supports the implication of SGs in chemoresistance. For instance, G3BP1 depletion sensitizes glioblastoma cell lines to Bortezomib treatment by suppressing SG assembly and glutamine deprivation overcomes chemoresistance in pancreatic cancer through inhibition of SG formation. However, the capacity of SG to confer cancer cells chemoresistance and survival advantage relies on the recruitment of a set of target RNAs to influence their expression/function. Until recently, the mechanism behind s","journal":"Clinical and Translational Medicine","year":2023,"id":378970,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":2,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9513,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2023-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":108562,"name":"Ying Qing","orcid":"0000-0001-6763-6204","position":1,"is_corresponding":false},{"id":87800,"name":"Xiaolan Deng","orcid":"0000-0003-3695-0203","position":2,"is_corresponding":false},{"id":87799,"name":"Rui Su","orcid":"0000-0002-4807-6229","position":3,"is_corresponding":false},{"id":106277,"name":"Jianjun Chen","orcid":"0000-0003-3749-2902","position":4,"is_corresponding":false},{"id":108559,"name":"Zhicong Zhao","orcid":"0000-0002-3225-2494","position":0,"is_corresponding":true}],"reference_count":9,"raw_metadata":null,"created_at":"2026-07-19T01:16:48.594070Z","pmid":"37667528","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}