| 1. |
|
|
| 2. |
- Achour, Cyrinne, et al.
(författare)
-
Long Noncoding RNAs as Players in Breast Tumorigenesis
- 2020
-
Ingår i: The chemical biology of long noncoding RNAs. - Cham : Springer. - 9783030447427 - 9783030447458 - 9783030447434 ; , s. 385-403
-
Bokkapitel (refereegranskat)abstract
- Comprehensive analysis of the mammalian genome uncovered the discovery of pervasive transcription of large RNA transcripts that do not code for proteins, namely, long noncoding RNAs (lncRNAs). LncRNAs play important roles in the regulation of gene expression from integration of chromatin remodeling complexes to transcriptional and posttranscriptional regulation of protein-coding genes. Application of next-generation sequencing technologies to cancer transcriptomes has revealed that aberrant expression of lncRNAs is associated with tumor progression and metastasis. Although thousands of lncRNAs have been shown to be dysregulated in different cancer types, just few of them have been fully characterized. In this book chapter, we aim to highlight recent findings of the mechanistic function of lncRNAs in breast cancer and summarize key examples of lncRNAs that are misregulated during breast tumorigenesis. We have categorized breast cancer–associated lncRNA according to their contribution to tumor suppression or tumor progression based on recent studies. Because some of them are expressed in a specific molecular breast cancer subtype, we have outlined lncRNAs that can potentially serve as diagnostic and prognostic markers, in which expression is linked to chemotherapy resistance. Finally, we have discussed current limitations and perspectives on potential lncRNA targets for use in therapies against breast cancer.
|
|
| 3. |
- Achour, Cyrinne, et al.
(författare)
-
METTL3 regulates breast cancer-associated alternative splicing switches
- 2023
-
Ingår i: Oncogene. - : Nature Publishing Group. - 0950-9232 .- 1476-5594. ; 42, s. 911-925
-
Tidskriftsartikel (refereegranskat)abstract
- Alternative splicing (AS) enables differential inclusion of exons from a given transcript, thereby contributing to the transcriptome and proteome diversity. Aberrant AS patterns play major roles in the development of different pathologies, including breast cancer. N6-methyladenosine (m6A), the most abundant internal modification of eukaryotic mRNA, influences tumor progression and metastasis of breast cancer, and it has been recently linked to AS regulation. Here, we identify a specific AS signature associated with breast tumorigenesis in vitro. We characterize for the first time the role of METTL3 in modulating breast cancer-associated AS programs, expanding the role of the m6A-methyltransferase in tumorigenesis. Specifically, we find that both m6A deposition in splice site boundaries and in splicing and transcription factor transcripts, such as MYC, direct AS switches of specific breast cancer-associated transcripts. Finally, we show that five of the AS events validated in vitro are associated with a poor overall survival rate for patients with breast cancer, suggesting the use of these AS events as a novel potential prognostic biomarker.
|
|
| 4. |
- Aguilo, Francesca, PhD, et al.
(författare)
-
Editorial : translational control in cancer
- 2024
-
Ingår i: NAR Cancer. - : Oxford University Press. - 2632-8674. ; 6:3
-
Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)
|
|
| 5. |
- Bhattarai, Devi Prasad, et al.
(författare)
-
m6A RNA immunoprecipitation followed by high-throughput sequencing to map N6-Methyladenosine
- 2022. - 3
-
Ingår i: Post-transcriptional gene regulation. - New York, NY : Humana Press. - 9781071618516 - 9781071618509 ; , s. 355-362
-
Bokkapitel (refereegranskat)abstract
- N6-methyladenosine (m6A) is the most abundant internal modification on messenger RNAs (mRNAs) and long noncoding RNAs (lncRNAs) in eukaryotes. It influences gene expression by regulating RNA processing, nuclear export, mRNA decay, and translation. Hence, m6A controls fundamental cellular processes, and dysregulated deposition of m6A has been acknowledged to play a role in a broad range of human diseases, including cancer. m6A RNA immunoprecipitation followed by high-throughput sequencing (MeRIP-seq or m6A-seq) is a powerful technique to map m6A in a transcriptome-wide level. After immunoprecipitation of fragmented polyadenylated (poly(A)+) rich RNA by using specific anti-m6A antibodies, both the immunoprecipitated RNA fragments together with the input control are subjected to massively parallel sequencing. The generation of such comprehensive methylation profiles of signal enrichment relative to input control is necessary in order to better comprehend the pathogenesis behind aberrant m6A deposition.
|
|
| 6. |
- Boccaletto, Pietro, et al.
(författare)
-
MODOMICS: a database of RNA modification pathways. 2021 update
- 2022
-
Ingår i: Nucleic Acids Research. - : Oxford University Press. - 0305-1048 .- 1362-4962. ; 50:D1, s. D231-D235
-
Tidskriftsartikel (refereegranskat)abstract
- The MODOMICS database has been, since 2006, a manually curated and centralized resource, storing and distributing comprehensive information about modified ribonucleosides. Originally, it only contained data on the chemical structures of modified ribonucleosides, their biosynthetic pathways, the location of modified residues in RNA sequences, and RNA-modifying enzymes. Over the years, prompted by the accumulation of new knowledge and new types of data, it has been updated with new information and functionalities. In this new release, we have created a catalog of RNA modifications linked to human diseases, e.g., due to mutations in genes encoding modification enzymes. MODOMICS has been linked extensively to RCSB Protein Data Bank, and sequences of experimentally determined RNA structures with modified residues have been added. This expansion was accompanied by including nucleotide 5'-monophosphate residues. We redesigned the web interface and upgraded the database backend. In addition, a search engine for chemically similar modified residues has been included that can be queried by SMILES codes or by drawing chemical molecules. Finally, previously available datasets of modified residues, biosynthetic pathways, and RNA-modifying enzymes have been updated. Overall, we provide users with a new, enhanced, and restyled tool for research on RNA modification. MODOMICS is available at https://iimcb.genesilico.pl/modomics/.
|
|
| 7. |
- Destefanis, Eliana, et al.
(författare)
-
A mark of disease : How mRNA modifications shape genetic and acquired pathologies
- 2021
-
Ingår i: RNA. - : Cold Spring Harbor Laboratory Press (CSHL). - 1355-8382 .- 1469-9001. ; 27:4, s. 367-389
-
Forskningsöversikt (refereegranskat)abstract
- RNA modifications have recently emerged as a widespread and complex facet of gene expression regulation. Counting more than 170 distinct chemical modifications with far-reaching implications for RNA fate, they are collectively referred to as the epitranscriptome. These modifications can occur in all RNA species, including messenger RNAs (mRNAs) and noncoding RNAs (ncRNAs). In mRNAs the deposition, removal, and recognition of chemical marks by writers, erasers and readers influence their structure, localization, stability, and translation. In turn, this modulates key molecular and cellular processes such as RNA metabolism, cell cycle, apoptosis, and others. Unsurprisingly, given their relevance for cellular and organismal functions, alterations of epitranscriptomic marks have been observed in a broad range of human diseases, including cancer, neurological and metabolic disorders. Here, we will review the major types of mRNA modifications and editing processes in conjunction with the enzymes involved in their metabolism and describe their impact on human diseases. We present the current knowledge in an updated catalog. We will also discuss the emerging evidence on the crosstalk of epitranscriptomic marks and what this interplay could imply for the dynamics of mRNA modifications. Understanding how this complex regulatory layer can affect the course of human pathologies will ultimately lead to its exploitation toward novel epitranscriptomic therapeutic strategies.
|
|
| 8. |
- Esteva-Socias, Margalida, et al.
(författare)
-
METTL3 as a master regulator of translation in cancer : mechanisms and implications
- 2024
-
Ingår i: NAR Cancer. - : Oxford University Press. - 2632-8674. ; 6:1
-
Tidskriftsartikel (refereegranskat)abstract
- Translational regulation is an important step in the control of gene expression. In cancer cells, the orchestration of both global control of protein synthesis and selective translation of specific mRNAs promote tumor cell survival, angiogenesis, transformation, invasion and metastasis. N6-methyladenosine (m6A), the most prevalent mRNA modification in higher eukaryotes, impacts protein translation. Over the past decade, the development of m6A mapping tools has facilitated comprehensive functional investigations, revealing the involvement of this chemical mark, together with its writer METTL3, in promoting the translation of both oncogenes and tumor suppressor transcripts, with the impact being context-dependent. This review aims to consolidate our current understanding of how m6A and METTL3 shape translation regulation in the realm of cancer biology. In addition, it delves into the role of cytoplasmic METTL3 in protein synthesis, operating independently of its catalytic activity. Ultimately, our goal is to provide critical insights into the interplay between m6A, METTL3 and translational regulation in cancer, offering a deeper comprehension of the mechanisms sustaining tumorigenesis.
|
|
| 9. |
- Jönsson, Johanna, 1993-
(författare)
-
The balance of splicing : A novel insight into the splicing regulation of high-risk HPV E6 and E7 oncogenes.
- 2023
-
Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- HPV is associated with several cancers. The genome consists of a long control region, early (E1, E2, E4, E5, E6 and E7) and late (L1 and L2) genes. The E6 and E7 proteins prevent cells from entering apoptosis and regulate the cell cycle. A deregulated expression of these can result in malignant transformations. Therefore, a deeper understanding of their regulation is important. HPV gene expression regulation occurs mainly through alternative pre-mRNA splicing with many splice events being mutually exclusive. This is the case with E6 and E7. E6 is expressed from the intron-retained mRNA while E7 is expressed from a spliced mRNA. In this thesis it was aimed to understand the alternative splice events of HPV16 E6 and E7 mRNAs by identifying regulatory elements controlling these splice events. A strong enhancer, downstream of SA409, was identified. It consists of a perfect bipartite repeat and mutations in the element disrupts SA409 splicing. Trans-acting factors were determined to TRAP150 and BCLAF1 (Paper I). Downstream of this is another cis-element. It consists of a GGGG-motif with a silencing effect on SA409 splicing. Two additional cis-elements, one at the end of the E6 ORF and the other at the start of the E7 ORF, were additionally found. These are suggested to hybridize forming an internal-loop structure when analyzed in silico. The cis-element at the end of the E6 ORF is context dependent, functioning as an enhancer or silencer depending on if the E7 cis-element is included or not. It was identified as ATCATCA (Paper III). The cis-element at the start of the E7 ORF was a silencer and consisted of an AUG-rich element. Two trans-acting factors interacted with it, hnRNP A1 and hnRNP A2, and prevented SA409 splicing. However, hnRNP A1 increased the intron-retained E6 mRNA, while hnRNP A2 redirected splicing to a downstream acceptor, SA742 (Paper IV). SA742 was additionally found to be regulated by another cis-element, within the E1 ORF. It consisted of three GGG/GGGG motifs and the integrity of these and of SD880 were important for SA742 usage, indicating the importance of regulatory factors in the modulation of the splicing modes: intron definition and exon definition. The trans-acting factor was hnRNP H (Paper II). In this thesis five cis-elements and five trans-acting factors affecting splicing regulation within the E6 and E7 ORFs were identified. With this knowledge to build upon several important targets to change or disrupt splicing were identified.
|
|
| 10. |
- Kumari, Kanchan, et al.
(författare)
-
Regulatory roles of RNA modifications in breast cancer
- 2021
-
Ingår i: NAR Cancer. - : Oxford University Press. - 2632-8674. ; 3:3
-
Forskningsöversikt (refereegranskat)abstract
- Collectively referred to as the epitranscriptome, RNA modifications play important roles in gene expression control regulating relevant cellular processes. In the last few decades, growing numbers of RNA modifications have been identified not only in abundant ribosomal (rRNA) and transfer RNA (tRNA) but also in messenger RNA (mRNA). In addition, many writers, erasers and readers that dynamically regulate the chemical marks have also been characterized. Correct deposition of RNA modifications is prerequisite for cellular homeostasis, and its alteration results in aberrant transcriptional programs that dictate human disease, including breast cancer, the most frequent female malignancy, and the leading cause of cancer-related death in women. In this review, we emphasize the major RNA modifications that are present in tRNA, rRNA and mRNA. We have categorized breast cancer-associated chemical marks and summarize their contribution to breast tumorigenesis. In addition, we describe less abundant tRNA modifications with related pathways implicated in breast cancer. Finally, we discuss current limitations and perspectives on epitranscriptomics for use in therapeutic strategies against breast and other cancers.
|
|
