Guardian ubiquitin E3 ligases target cancer-associated APOBEC3 deaminases for degradation to promote human genome integrity DOI Creative Commons
Irene Schwartz, Valentina Budroni,

Mathilde Meyenberg

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: April 26, 2024

Abstract Highlights RNA-free APOBEC3 (A3) can enter the nucleus, leading to genomic mutations. Three E3 ligases specifically bind RNA-binding domain of nuclear A3s. Cancer-associated A3B and A3H-I are thereby targeted for proteasomal degradation. These thus act as genome guardians by limiting A3-mediated mutagenesis. APOBEC family members play crucial roles in antiviral restriction. However, certain proteins drive harmful hypermutation humans, contributing cancer. The cancer-associated A3 capable transiting from cytosol where they cause Here, we uncover a specific set cellular pathways that protect DNA major proteins. Through genetic proteomic screening identify UBR4, UBR5, HUWE1 key ubiquitin marking degradation, A3-driven hypermutation. Mechanistically, UBR5 recognize unoccupied domains, promoting degradation protein is not engaged its function. Depletion or mutation cells human cancer samples increases Our findings reveal factors ubiquitination cascade maintains stability.

Language: Английский

Unveiling the Global Surge of Mpox (Monkeypox): A comprehensive review of current evidence DOI Creative Commons
Phelipe Magalhães Duarte, Ridwan Olamilekan Adesola, Swagatika Priyadarsini

et al.

The Microbe, Journal Year: 2024, Volume and Issue: 4, P. 100141 - 100141

Published: Aug. 17, 2024

Monkeypox, now named mpox, has emerged as a significant public threat, evidenced by the 2022 outbreak affecting over seventy countries globally. This infectious disease presents debilitating symptoms, including painful skin rashes, mucosal lesions, enlarged lymph nodes, and fever. The situation intensifies with concerns about novel transmission route, specifically through sexual contact, evolution of more transmissible strains. Complicating matters further is documented spillback mpox from humans to animals, raising potential for new animal reservoirs. study utilized systematic approach gather, analyse, interpret data regarding global outbreaks, phylogenomics, human APOBEC3 enzyme activity, antiviral resistance issues, application One Health intervention. Emphasizing covers various aspects, zoonotic origins, pathogenesis, changing epidemiological landscapes, phylogenomic diversity, clade dynamics. review underscores crucial role collaboration in understanding combatting making it valuable resource shaping effective prevention control measures on scale.

Language: Английский

Citations

19
Inferring active mutational processes in cancer using single cell sequencing and evolutionary constraints DOI Creative Commons
Gryte Satas, Matthew A. Myers, Andrew McPherson

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 27, 2025

Ongoing mutagenesis in cancer drives genetic diversity throughout the natural history of cancers. As activities mutational processes are dynamic evolution, distinguishing signatures 'active' and 'historical' has important implications for studying how tumors evolve. This can aid understanding mutagenic states at time presentation, associating active process with therapeutic resistance. bulk sequencing primarily captures historical processes, we studied whether ultra-low-coverage single-cell whole-genome (scWGS), which measures distribution mutations across hundreds or thousands individual cells, could enable distinction between processes. While technical challenges data sparsity have limited mutation analysis scWGS, show that these contain valuable information about To robustly interpret single nucleotide variants (SNVs) introduce ArtiCull, a method to identify remove SNV artifacts by leveraging evolutionary constraints, enabling reliable detection signature analysis. Applying this approach scWGS from pancreatic ductal adenocarcinoma (PDAC), triple-negative breast (TNBC), high-grade serous ovarian (HGSOC), uncover temporal spatial patterns In PDAC, observe increase mismatch repair deficiency (MMRd). cisplatin-treated TNBC patient-derived xenografts, therapy-induced inactivation APOBEC3 activity. HGSOC, distinct mutagenesis, including late tumor-wide activation one case clade-specific enrichment another. Additionally, detect clone-specific SBS17 activity, clone previously linked recurrence. Our findings establish as powerful may influence ongoing clonal evolution

Language: Английский

Citations

0
APOBEC3 Proteins: From Antiviral Immunity to Oncogenic Drivers in HPV-Positive Cancers DOI Creative Commons
Eliza Pizarro Castilha,

Rosalba Biondo,

Kleber Paiva Trugilo

et al.

Viruses, Journal Year: 2025, Volume and Issue: 17(3), P. 436 - 436

Published: March 18, 2025

The human APOBEC superfamily consists of eleven cytidine deaminase enzymes. Among them, APOBEC3 enzymes play a dual role in antiviral immunity and cancer development. enzymes, including APOBEC3A (A3A) APOBEC3B (A3B), induce mutations viral DNA, effectively inhibiting replication but also promoting somatic the host genome, contributing to A3A A3B are linked mutational signatures over 50% cancers, with being potent mutagen. A3B, one first carcinogenesis, plays significant HPV-associated cancers by driving mutagenesis tumor progression. A3A_B deletion polymorphism results hybrid gene, leading increased expression enhanced mutagenic potential. Such has been an elevated risk certain particularly populations where it is more prevalent. This review explores molecular mechanisms proteins, highlighting their roles defense tumorigenesis. We discuss clinical implications genetic variants, such as polymorphism, mainly HPV infection associated providing comprehensive understanding contributions both restriction

Language: Английский

Citations

0
Mutational landscapes of brain metastases across various histological subtypes of lung cancer DOI Creative Commons
Marcin Nicoś, Tomasz Stokowy, Katarzyna Reszka

et al.

Research Square (Research Square), Journal Year: 2025, Volume and Issue: unknown

Published: March 21, 2025

Abstract The knowledge of the genetic landscape lung cancer brain metastases (BM) is scarce due to low availability intracranial samples. Here, we investigated features 142 BM by next-generation sequencing in various histological subtypes (19 small-cell (SCLC), 123 from non-small-cell (NSCLC) including 79 adenocarcinomas (LUAD), 31 squamous carcinomas (LUSC), and 13 large-cell (LCLC). TP53, H3F3A, PMS2 genes were mutated over 20% BM, irrespective their primary histology. LUAD-BM harbored a broad repertoire proto-oncogenes with tyrosine kinase activity was significantly associated APOBEC enrichment PTEN, EGFR, NF1 gene mutations. TP53 RB1 most frequently suppressor SCLC-BM. Gene Ontology analysis indicated that SCLC-BM LCLC-BM deregulated glial proliferation processes. These findings provide comprehensive genomic characterization histologies.

Language: Английский

Citations

0
APOBEC3A, not APOBEC3B, drives deaminase mutagenesis in human gastric epithelium DOI Creative Commons
Yohan An, Ji‐Hyun Lee, Joonoh Lim

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: Oct. 31, 2024

Abstract Cancer genomes frequently carry APOBEC (apolipoprotein B mRNA editing catalytic polypeptide-like)-associated DNA mutations, suggesting enzymes as innate mutagens during cancer initiation and/or evolution. However, the pure mutagenic impacts of specific among this family that are responsible for APOBEC-associated mutagenesis remain unclear, particularly comparative activities APOBEC3A and APOBEC3B . Here, we investigated contributions these through whole-genome sequencing human normal gastric organoid lines carrying doxycycline-inducible or cassettes. Our findings demonstrated transcriptional upregulation led to acquisition a massive number genomic mutations in few cell cycles. By contrast, did not generate substantial epithelium. -associated remained insignificant even after combined inactivation TP53 Based on spectrum acquired upregulation, further analyzed mutational signatures, encompassing indels mainly composed 1bp deletions, characteristics clustered selective pressures operative cells mutations. observations provide clear foundation understanding impact cells.

Language: Английский

Citations

0
Guardian ubiquitin E3 ligases target cancer-associated APOBEC3 deaminases for degradation to promote human genome integrity DOI Creative Commons
Irene Schwartz, Valentina Budroni,

Mathilde Meyenberg

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: April 26, 2024

Abstract Highlights RNA-free APOBEC3 (A3) can enter the nucleus, leading to genomic mutations. Three E3 ligases specifically bind RNA-binding domain of nuclear A3s. Cancer-associated A3B and A3H-I are thereby targeted for proteasomal degradation. These thus act as genome guardians by limiting A3-mediated mutagenesis. APOBEC family members play crucial roles in antiviral restriction. However, certain proteins drive harmful hypermutation humans, contributing cancer. The cancer-associated A3 capable transiting from cytosol where they cause Here, we uncover a specific set cellular pathways that protect DNA major proteins. Through genetic proteomic screening identify UBR4, UBR5, HUWE1 key ubiquitin marking degradation, A3-driven hypermutation. Mechanistically, UBR5 recognize unoccupied domains, promoting degradation protein is not engaged its function. Depletion or mutation cells human cancer samples increases Our findings reveal factors ubiquitination cascade maintains stability.

Language: Английский

Citations

0