Targeting natural splicing plasticity of APOBEC3B restricts its expression and mutagenic activity

Banday, Abdul Rouf; Onabajo, Olusegun O.; Lin, Seraph Han-Yin; Obajemu, Adeola; Vargas, Joselin M.; Delviks-Frankenberry, Krista A.; Lamy, Philippe; Bayanjargal, Ariunaa; Zettelmeyer, Clara; Flórez-Vargas, Óscar; Pathak, Vinay K.; Dyrskjøt, Lars; Prokunina‐Olsson, Ludmila

doi:10.1038/s42003-021-01844-5

Cited by 7 publications

(12 citation statements)

References 64 publications

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“…High APOBEC3B expression was also associated with more APOBEC3-induced mutations in lung cancer, while both APOBEC3A and APOBEC3B levels were correlated with APOBEC3-induced mutations in breast cancer [ 22 , 47 , 53 , 54 ]. Similar associations have been observed in bladder cancer, which has one of the highest APOBEC3-induced mutation burden [ 1 , 27 , 34 , 46 ]. In cholangiocarcinoma, only APOBEC3A expression was associated with APOBEC3-induced mutation burden [ 43 ].…”

Section: Introductionsupporting

confidence: 78%

“…Exposure to certain drugs can also trigger APOBEC3-mediated mutagenesis, and chemotherapies such as bleomycin, cisplatin, etoposide, 5-fluorouracil, gemcitabine, hydroxyurea, aphidicolin, and camptothecin have all been shown to induce APOBEC3 expression in cancer cell lines [ 1 , 61 , 90 , 91 ]. NF-κB signaling likely mediates APOBEC3 induction in response to some of these drugs, but replication stress and PI3K signaling may also play major role (Fig.…”

Section: Exogenous and Endogenous Triggers Of Apobec3-mediated Mutage...mentioning

confidence: 99%

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APOBEC3-mediated mutagenesis in cancer: causes, clinical significance and therapeutic potential

Butler

Banday

2023

J Hematol Oncol

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Apolipoprotein B mRNA-editing enzyme, catalytic polypeptides (APOBECs) are cytosine deaminases involved in innate and adaptive immunity. However, some APOBEC family members can also deaminate host genomes to generate oncogenic mutations. The resulting mutations, primarily signatures 2 and 13, occur in many tumor types and are among the most common mutational signatures in cancer. This review summarizes the current evidence implicating APOBEC3s as major mutators and outlines the exogenous and endogenous triggers of APOBEC3 expression and mutational activity. The review also discusses how APOBEC3-mediated mutagenesis impacts tumor evolution through both mutagenic and non-mutagenic pathways, including by inducing driver mutations and modulating the tumor immune microenvironment. Moving from molecular biology to clinical outcomes, the review concludes by summarizing the divergent prognostic significance of APOBEC3s across cancer types and their therapeutic potential in the current and future clinical landscapes.

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Section: Introductionsupporting

confidence: 78%

Section: Exogenous and Endogenous Triggers Of Apobec3-mediated Mutage...mentioning

confidence: 99%

APOBEC3-mediated mutagenesis in cancer: causes, clinical significance and therapeutic potential

Butler

Banday

2023

J Hematol Oncol

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“…Specifically, since MM patients with high APOBEC activity have a poor prognosis, it was suggested they might benefit from more aggressive treatments. It is worth noting that approaches are being developed to target APOBEC enzymes [ 471 ].…”

Section: Mutational Signatures In MM Genomesmentioning

confidence: 99%

Genome Instability in Multiple Myeloma: Facts and Factors

Aksenova

Zhuk

Lada

et al. 2021

Cancers

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Multiple myeloma (MM) is a malignant neoplasm of terminally differentiated immunoglobulin-producing B lymphocytes called plasma cells. MM is the second most common hematologic malignancy, and it poses a heavy economic and social burden because it remains incurable and confers a profound disability to patients. Despite current progress in MM treatment, the disease invariably recurs, even after the transplantation of autologous hematopoietic stem cells (ASCT). Biological processes leading to a pathological myeloma clone and the mechanisms of further evolution of the disease are far from complete understanding. Genetically, MM is a complex disease that demonstrates a high level of heterogeneity. Myeloma genomes carry numerous genetic changes, including structural genome variations and chromosomal gains and losses, and these changes occur in combinations with point mutations affecting various cellular pathways, including genome maintenance. MM genome instability in its extreme is manifested in mutation kataegis and complex genomic rearrangements: chromothripsis, templated insertions, and chromoplexy. Chemotherapeutic agents used to treat MM add another level of complexity because many of them exacerbate genome instability. Genome abnormalities are driver events and deciphering their mechanisms will help understand the causes of MM and play a pivotal role in developing new therapies.

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“…The canonical and non-canonical NF-κB pathway and b-Myb enhance A3B transcription, while E2F complexes suppress it 8 – 11 . Post-transcriptional regulatory mechanisms include protein kinase A mediated phosphorylation which inhibits A3B mutagenic activity 12 and alternative splicing of A3B which creates non-mutagenic isoforms 13 .…”

Section: Introductionmentioning

confidence: 99%

ILF2 enhances the DNA cytosine deaminase activity of tumor mutator APOBEC3B in multiple myeloma cells

Kazuma

Shirakawa

Tashiro

et al. 2022

Sci Rep

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DNA cytosine deaminase APOBEC3B (A3B) is an endogenous source of mutations in many human cancers, including multiple myeloma. A3B proteins form catalytically inactive high molecular mass (HMM) complexes in nuclei, however, the regulatory mechanisms of A3B deaminase activity in HMM complexes are still unclear. Here, we performed mass spectrometry analysis of A3B-interacting proteins from nuclear extracts of myeloma cell lines and identified 30 putative interacting proteins. These proteins are involved in RNA metabolism, including RNA binding, mRNA splicing, translation, and regulation of gene expression. Except for SAFB, these proteins interact with A3B in an RNA-dependent manner. Most of these interacting proteins are detected in A3B HMM complexes by density gradient sedimentation assays. We focused on two interacting proteins, ILF2 and SAFB. We found that overexpressed ILF2 enhanced the deaminase activity of A3B by 30%, while SAFB did not. Additionally, siRNA-mediated knockdown of ILF2 suppressed A3B deaminase activity by 30% in HEK293T cell lysates. Based on these findings, we conclude that ILF2 can interact with A3B and enhance its deaminase activity in HMM complexes.

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Targeting natural splicing plasticity of APOBEC3B restricts its expression and mutagenic activity

Cited by 7 publications

References 64 publications

APOBEC3-mediated mutagenesis in cancer: causes, clinical significance and therapeutic potential

APOBEC3-mediated mutagenesis in cancer: causes, clinical significance and therapeutic potential

Genome Instability in Multiple Myeloma: Facts and Factors

ILF2 enhances the DNA cytosine deaminase activity of tumor mutator APOBEC3B in multiple myeloma cells

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