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Publications (10 of 57) Show all publications
Zavadil, F., Henek, T., Habault, J., Chemali, R., Tovar-Fernandez, M. C., Daskalogianni, C., . . . Fåhraeus, R. (2025). Translation of bi-directional transcripts enhances MHC-I peptide diversity. Frontiers in Immunology, 16, Article ID 1554561.
Open this publication in new window or tab >>Translation of bi-directional transcripts enhances MHC-I peptide diversity
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2025 (English)In: Frontiers in Immunology, E-ISSN 1664-3224, Vol. 16, article id 1554561Article in journal (Refereed) Published
Abstract [en]

Antisense transcripts play an important role in generating regulatory non-coding RNAs but whether these transcripts are also translated to generate functional peptides remains poorly understood. In this study, RNA sequencing and six-frame database generation were combined with mass spectrometry analysis of peptides isolated from polysomes to identify Nascent Pioneer Translation Products (Na-PTPs) originating from alternative reading frames of bi-directional transcripts. Two Na-PTP originating peptides derived from antisense strands stimulated CD8+ T cell proliferation when presented to peripheral blood mononuclear cells (PBMCs) from nine healthy donors. Importantly, an antigenic peptide derived from the reverse strand of two cDNA constructs was presented on MHC-I molecules and induced CD8+ T cell activation. The results demonstrate that three-frame translation of bi-directional transcripts generates antigenic peptide substrates for the immune system. This discovery holds significance for understanding the origin of self-discriminating peptide substrates for the major histocompatibility class I (MHC-I) pathway and for enhancing immune-based therapies against infected or transformed cells.

Place, publisher, year, edition, pages
Frontiers Media S.A., 2025
Keywords
bi-directional transcripts, bi-directional translation, MHC-I epitope, Pioneer Translation Products, reverse strand antigenic peptides
National Category
Immunology in the Medical Area Immunology
Identifiers
urn:nbn:se:umu:diva-237344 (URN)10.3389/fimmu.2025.1554561 (DOI)001455088300001 ()40165968 (PubMedID)2-s2.0-105001448358 (Scopus ID)
Available from: 2025-04-23 Created: 2025-04-23 Last updated: 2025-04-23Bibliographically approved
Fåhraeus, R. (2024). Has translation in the nucleus found its purpose?. Nature reviews. Molecular cell biology, 25(1), 1-2
Open this publication in new window or tab >>Has translation in the nucleus found its purpose?
2024 (English)In: Nature reviews. Molecular cell biology, ISSN 1471-0072, E-ISSN 1471-0080, Vol. 25, no 1, p. 1-2Article in journal, Editorial material (Other academic) Published
Place, publisher, year, edition, pages
Springer Nature, 2024
National Category
Cell Biology Cell and Molecular Biology
Identifiers
urn:nbn:se:umu:diva-213726 (URN)10.1038/s41580-023-00651-6 (DOI)001050037200001 ()37592061 (PubMedID)2-s2.0-85168121978 (Scopus ID)
Available from: 2023-09-06 Created: 2023-09-06 Last updated: 2025-04-14Bibliographically approved
López, I., Valdivia, I. L., Vojtesek, B., Fåhraeus, R. & Coates, P. J. (2024). Re-appraising the evidence for the source, regulation and function of p53-family isoforms. Nucleic Acids Research, 52(20), 12112-12129
Open this publication in new window or tab >>Re-appraising the evidence for the source, regulation and function of p53-family isoforms
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2024 (English)In: Nucleic Acids Research, ISSN 0305-1048, E-ISSN 1362-4962, Vol. 52, no 20, p. 12112-12129Article, review/survey (Refereed) Published
Abstract [en]

The p53 family of proteins evolved from a common ancestor into three separate genes encoding proteins that act as transcription factors with distinct cellular roles. Isoforms of each member that lack specific regions or domains are suggested to result from alternative transcription start sites, alternative splicing or alternative translation initiation, and have the potential to exponentially increase the functional repertoire of each gene. However, evidence supporting the presence of individual protein variants at functional levels is often limited and is inferred by mRNA detection using highly sensitive amplification techniques. We provide a critical appraisal of the current evidence for the origins, expression, functions and regulation of p53-family isoforms. We conclude that despite the wealth of publications, several putative isoforms remain poorly established. Future research with improved technical approaches and the generation of isoform-specific protein detection reagents is required to establish the physiological relevance of p53-family isoforms in health and disease. In addition, our analyses suggest that p53-family variants evolved partly through convergent rather than divergent evolution from the ancestral gene.

Place, publisher, year, edition, pages
Oxford University Press, 2024
National Category
Biochemistry Molecular Biology
Identifiers
urn:nbn:se:umu:diva-232417 (URN)10.1093/nar/gkae855 (DOI)001332583500001 ()39404067 (PubMedID)2-s2.0-85208771701 (Scopus ID)
Funder
Cancerforskningsfonden i NorrlandSwedish Cancer SocietySwedish Research Council
Available from: 2024-12-02 Created: 2024-12-02 Last updated: 2025-03-25Bibliographically approved
Karakostis, K., Malbert-Colas, L., Thermou, A., Vojtesek, B. & Fåhraeus, R. (2024). The DNA damage sensor ATM kinase interacts with the p53 mRNA and guides the DNA damage response pathway. Molecular Cancer, 23(1), Article ID 21.
Open this publication in new window or tab >>The DNA damage sensor ATM kinase interacts with the p53 mRNA and guides the DNA damage response pathway
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2024 (English)In: Molecular Cancer, E-ISSN 1476-4598, Vol. 23, no 1, article id 21Article in journal (Refereed) Published
Abstract [en]

Background: The ATM kinase constitutes a master regulatory hub of DNA damage and activates the p53 response pathway by phosphorylating the MDM2 protein, which develops an affinity for the p53 mRNA secondary structure. Disruption of this interaction prevents the activation of the nascent p53. The link of the MDM2 protein—p53 mRNA interaction with the upstream DNA damage sensor ATM kinase and the role of the p53 mRNA in the DNA damage sensing mechanism, are still highly anticipated.

Methods: The proximity ligation assay (PLA) has been extensively used to reveal the sub-cellular localisation of the protein—mRNA and protein–protein interactions. ELISA and co-immunoprecipitation confirmed the interactions in vitro and in cells.

Results: This study provides a novel mechanism whereby the p53 mRNA interacts with the ATM kinase enzyme and shows that the L22L synonymous mutant, known to alter the secondary structure of the p53 mRNA, prevents the interaction. The relevant mechanistic roles in the DNA Damage Sensing pathway, which is linked to downstream DNA damage response, are explored. Following DNA damage (double-stranded DNA breaks activating ATM), activated MDMX protein competes the ATM—p53 mRNA interaction and prevents the association of the p53 mRNA with NBS1 (MRN complex). These data also reveal the binding domains and the phosphorylation events on ATM that regulate the interaction and the trafficking of the complex to the cytoplasm.

Conclusion: The presented model shows a novel interaction of ATM with the p53 mRNA and describes the link between DNA Damage Sensing with the downstream p53 activation pathways; supporting the rising functional implications of synonymous mutations altering secondary mRNA structures.

Place, publisher, year, edition, pages
Springer Nature, 2024
Keywords
DNA Damage Sensing, Genotoxic stress, MDM2, MRN complex, Precision medicine, RNA secondary structure, Synonymous mutations
National Category
Biochemistry Molecular Biology Cell Biology
Identifiers
urn:nbn:se:umu:diva-220442 (URN)10.1186/s12943-024-01933-z (DOI)001148329800001 ()38263180 (PubMedID)2-s2.0-85183003442 (Scopus ID)
Funder
Cancerforskningsfonden i NorrlandSwedish Cancer Society
Available from: 2024-02-07 Created: 2024-02-07 Last updated: 2025-03-25Bibliographically approved
Karakostis, K., Padariya, M., Thermou, A., Fåhraeus, R., Kalathiya, U. & Vollrath, F. (2024). Thermal stress, p53 structures and learning from elephants. Cell Death Discovery, 10(1), Article ID 353.
Open this publication in new window or tab >>Thermal stress, p53 structures and learning from elephants
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2024 (English)In: Cell Death Discovery, E-ISSN 2058-7716, Vol. 10, no 1, article id 353Article in journal (Refereed) Published
Abstract [en]

As species adapt to climatic changes, temperature-dependent functions of p53 in development, metabolism and cancer will adapt as well. Structural analyses of p53 epitopes interacting in response to environmental stressors, such as heat, may uncover physiologically relevant functions of p53 in cell regulation and genomic adaptations. Here we explore the multiple p53 elephant paradigm with an experimentally validated in silico model showing that under heat stress some p53 copies escape negative regulation by the MDM2 E3 ubiquitin ligase. Multiple p53 isoforms have evolved naturally in the elephant thus presenting a unique experimental system to study the scope of p53 functions and the contribution of environmental stressors to DNA damage. We assert that fundamental insights derived from studies of a historically heat-challenged mammal will provide important insights directly relevant to human biology in the light of climate change when ‘heat’ may introduce novel challenges to our bodies and health.

Place, publisher, year, edition, pages
Springer Nature, 2024
National Category
Cell Biology Biochemistry Molecular Biology
Identifiers
urn:nbn:se:umu:diva-228476 (URN)10.1038/s41420-024-02109-w (DOI)001284933100001 ()39107279 (PubMedID)2-s2.0-85200677295 (Scopus ID)
Funder
European Regional Development Fund (ERDF), CZ.02.1.01/0.0/0.0/16_019/0000868Cancerforskningsfonden i NorrlandSwedish Cancer Society, 160598Swedish Research Council
Available from: 2024-08-15 Created: 2024-08-15 Last updated: 2025-03-25Bibliographically approved
Apcher, S., Vojtesek, B. & Fåhraeus, R. (2023). In search of the cell biology for self- versus non-self- recognition. Current Opinion in Immunology, 83, Article ID 102334.
Open this publication in new window or tab >>In search of the cell biology for self- versus non-self- recognition
2023 (English)In: Current Opinion in Immunology, ISSN 0952-7915, E-ISSN 1879-0372, Vol. 83, article id 102334Article, review/survey (Refereed) Published
Abstract [en]

Several of today's cancer treatments are based on the immune system's capacity to detect and destroy cells expressing neoantigens on major histocompatibility class-I molecules (MHC-I). Despite this, we still do not know the cell biology behind how antigenic peptide substrates (APSs) for the MHC-I pathway are produced. Indeed, there are few research fields with so many divergent views as the one concerning the source of APSs. This is quite remarkable considering their fundamental role in the immune systems’ capacity to detect and destroy virus-infected or transformed cells. A better understanding of the processes generating APSs and how these are regulated will shed light on the evolution of self-recognition and provide new targets for therapeutic intervention. We discuss the search for the elusive source of MHC-I peptides and highlight the cell biology that is still missing to explain how they are synthesised and where they come from.

National Category
Immunology in the medical area
Identifiers
urn:nbn:se:umu:diva-209275 (URN)10.1016/j.coi.2023.102334 (DOI)001009349500001 ()2-s2.0-85159605217 (Scopus ID)
Funder
Cancerforskningsfonden i NorrlandSwedish Cancer Society, 160598Swedish Cancer Society, 222505Swedish Research Council
Available from: 2023-06-08 Created: 2023-06-08 Last updated: 2024-03-26Bibliographically approved
Sroka, E. M., Lavigne, M., Pla, M., Daskalogianni, C., Tovar-Fernandez, M. C., Prado Martins, R., . . . Fåhraeus, R. (2023). Major histocompatibility class I antigenic peptides derived from translation of pre-mRNAs generate immune tolerance. Proceedings of the National Academy of Sciences of the United States of America, 120(7), Article ID e2208509120.
Open this publication in new window or tab >>Major histocompatibility class I antigenic peptides derived from translation of pre-mRNAs generate immune tolerance
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2023 (English)In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 120, no 7, article id e2208509120Article in journal (Refereed) Published
Abstract [en]

Antigenic peptides derived from introns are presented on major histocompatibility (MHC) class I molecules, but how these peptides are produced is poorly understood. Here, we show that an MHC class I epitope (SL8) sequence inserted in the second intron of the β-globin gene in a C57BL/6 mouse (HBB) generates immune tolerance. Introduction of SL8-specific CD8+ T cells derived from OT-1 transgenic mice resulted in a threefold increase in OT-1 T cell proliferation in HBB animals, as compared to wild-type animals. The growth of MCA sarcoma cells expressing the intron-derived SL8 epitope was suppressed in wild-type animals compared to HBB mice. The β-globin pre-mRNA was detected in the light polysomal fraction, and introducing stop codons identified a non-AUG initiation site between +228 and +255 nts upstream of the SL8. Isolation of ribosome footprints confirmed translation initiation within this 27 nt sequence. Furthermore, treatment with splicing inhibitor shifts the translation of the pre-mRNA to monosomal fractions and results in an increase of intron-derived peptide substrate as shown by polysome profiling and cell imaging. These results show that non-AUG-initiated translation of pre-mRNAs generates peptides for MHC class I immune tolerance and helps explain why alternative tissue-specific splicing is tolerated by the immune system.

Place, publisher, year, edition, pages
Proceedings of the National Academy of Sciences, 2023
Keywords
immune tolerance, MHC class I antigen presentation, mRNA translation
National Category
Immunology in the medical area
Identifiers
urn:nbn:se:umu:diva-204738 (URN)10.1073/pnas.2208509120 (DOI)001087245500002 ()36745791 (PubMedID)2-s2.0-85147460949 (Scopus ID)
Funder
Cancerforskningsfonden i NorrlandSwedish Cancer Society, 160598Swedish Research Council
Available from: 2023-02-23 Created: 2023-02-23 Last updated: 2025-04-24Bibliographically approved
Salomao, N., Maslah, N., Giulianelli, A., Drevon, L., Aguinaga, L., Gu, X., . . . Fåhraeus, R. (2023). Reduced murine double minute 2 and 4 protein, but not messenger RNA, expression is associated with more severe disease in myelodysplastic syndromes and acute myeloblastic leukaemia. British Journal of Haematology, 201(2), 234-248
Open this publication in new window or tab >>Reduced murine double minute 2 and 4 protein, but not messenger RNA, expression is associated with more severe disease in myelodysplastic syndromes and acute myeloblastic leukaemia
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2023 (English)In: British Journal of Haematology, ISSN 0007-1048, E-ISSN 1365-2141, Vol. 201, no 2, p. 234-248Article in journal (Refereed) Published
Abstract [en]

The human homologues of murine double minute 2 (MDM2) and 4 (MDM4) negatively regulate p53 tumour suppressor activity and are reported to be frequently overexpressed in human malignancies, prompting clinical trials with drugs that prevent interactions between MDM2/MDM4 and p53. Bone marrow samples from 111 patients with acute myeloblastic leukaemia, myelodysplastic syndrome or chronic myelomonocytic leukaemia were examined for protein (fluorescence-activated cell sorting) and messenger RNA (mRNA) expression (quantitative polymerase chain reaction) of MDM2, MDM4 and tumour protein p53 (TP53). Low protein expression of MDM2 and MDM4 was observed in immature cells from patients with excess of marrow blasts (>5%) compared with CD34+/CD45low cells from healthy donors and patients without excess of marrow blasts (<5%). The mRNA levels were indistinguishable in all samples examined regardless of disease status or blast levels. Low MDM2 and MDM4 protein expression were correlated with poor survival. These data show a poor correlation between mRNA and protein expression levels, suggesting that quantitative flow cytometry analysis of protein expression levels should be used to predict and validate the efficacy of MDM2 and MDM4 inhibitors. These findings show that advanced disease is associated with reduced MDM2 and MDM4 protein expression and indicate that the utility of MDM2 and MDM4 inhibitors may have to be reconsidered in the treatment of advanced myeloid malignancies.

Place, publisher, year, edition, pages
John Wiley & Sons, 2023
Keywords
acute myeloid leukaemia, murine double minute 2 (MDM2), murine double minute 4 (MDM4), myelodysplastic syndrome, p53
National Category
Hematology Cell and Molecular Biology
Identifiers
urn:nbn:se:umu:diva-202253 (URN)10.1111/bjh.18608 (DOI)000901620500001 ()36546586 (PubMedID)2-s2.0-85145072715 (Scopus ID)
Funder
European Regional Development Fund (ERDF), CZ.02.1.01/0.0/0.0/16_019/0000868Swedish Cancer SocietyCancerforskningsfonden i Norrland, 160598Swedish Research Council
Available from: 2023-01-05 Created: 2023-01-05 Last updated: 2023-07-14Bibliographically approved
Fusée, L., Salomao, N., Ponnuswamy, A., Wang, L., López, I., Chen, S., . . . Fåhraeus, R. (2023). The p53 endoplasmic reticulum stress-response pathway evolved in humans but not in mice via PERK-regulated p53 mRNA structures. Cell Death and Differentiation, 30, 1072-1081
Open this publication in new window or tab >>The p53 endoplasmic reticulum stress-response pathway evolved in humans but not in mice via PERK-regulated p53 mRNA structures
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2023 (English)In: Cell Death and Differentiation, ISSN 1350-9047, E-ISSN 1476-5403, Vol. 30, p. 1072-1081Article in journal (Refereed) Published
Abstract [en]

Cellular stress conditions activate p53-dependent pathways to counteract the inflicted damage. To achieve the required functional diversity, p53 is subjected to numerous post-translational modifications and the expression of isoforms. Little is yet known how p53 has evolved to respond to different stress pathways. The p53 isoform p53/47 (p47 or ΔNp53) is linked to aging and neural degeneration and is expressed in human cells via an alternative cap-independent translation initiation from the 2nd in-frame AUG at codon 40 (+118) during endoplasmic reticulum (ER) stress. Despite an AUG codon in the same location, the mouse p53 mRNA does not express the corresponding isoform in either human or mouse-derived cells. High-throughput in-cell RNA structure probing shows that p47 expression is attributed to PERK kinase-dependent structural alterations in the human p53 mRNA, independently of eIF2α. These structural changes do not take place in murine p53 mRNA. Surprisingly, PERK response elements required for the p47 expression are located downstream of the 2nd AUG. The data show that the human p53 mRNA has evolved to respond to PERK-mediated regulation of mRNA structures in order to control p47 expression. The findings highlight how p53 mRNA co-evolved with the function of the encoded protein to specify p53-activities under different cellular conditions.

Place, publisher, year, edition, pages
Springer Nature, 2023
National Category
Cell and Molecular Biology Biochemistry Molecular Biology
Identifiers
urn:nbn:se:umu:diva-205356 (URN)10.1038/s41418-023-01127-y (DOI)000937073800002 ()36813920 (PubMedID)2-s2.0-85148504831 (Scopus ID)
Funder
Cancerforskningsfonden i Norrland, LP 21-2270European Regional Development Fund (ERDF), CZ.02.1.01/0.0/0.0/16_019/0000868Swedish Cancer Society, 180296Swedish Cancer Society, 19 0073 Pj 01 HSwedish Research CouncilThe Kempe Foundations, SMK1864Cancerforskningsfonden i Norrland, AMP 22-1076
Available from: 2023-03-30 Created: 2023-03-30 Last updated: 2025-02-20Bibliographically approved
Calderon-González, K. G., Medina-Medina, I., Haronikova, L., Hernychova, L., Bonczek, O., Uhrik, L., . . . Olivares-Illana, V. (2022). Cryptic in vitro ubiquitin ligase activity of HDMX towards p53 is probably regulated by an induced fit mechanism. Bioscience Reports, 42(7), Article ID BSR20220186.
Open this publication in new window or tab >>Cryptic in vitro ubiquitin ligase activity of HDMX towards p53 is probably regulated by an induced fit mechanism
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2022 (English)In: Bioscience Reports, ISSN 0144-8463, E-ISSN 1573-4935, Vol. 42, no 7, article id BSR20220186Article in journal (Refereed) Published
Abstract [en]

HDMX and its homologue HDM2 are two essential proteins for the cell; after genotoxic stress, both are phosphorylated near to their RING domain, specifically at serine 403 and 395, respectively. Once phosphorylated, both can bind the p53 mRNA and enhance its translation; however, both recognize p53 protein and provoke its degradation under normal conditions. HDM2 has been well-recognized as an E3 ubiquitin ligase, whereas it has been reported that even with the high similarity between the RING domains of the two homologs, HDMX does not have the E3 ligase activity. Despite this, HDMX is needed for the proper p53 poly-ubiquitination. Phosphorylation at serine 395 changes the conformation of HDM2, helping to explain the switch in its activity, but no information on HDMX has been published. Here, we study the conformation of HDMX and its phospho-mimetic mutant S403D, investigate its E3 ligase activity and dissect its binding with p53. We show that phospho-mutation does not change the conformation of the protein, but HDMX is indeed an E3 ubiquitin ligase in vitro; however, in vivo, no activity was found. We speculated that HDMX is regulated by induced fit, being able to switch activity accordingly to the specific partner as p53 protein, p53 mRNA or HDM2. Our results aim to contribute to the elucidation of the contribution of the HDMX to p53 regulation.

Place, publisher, year, edition, pages
Portland Press, 2022
National Category
Biochemistry Molecular Biology
Identifiers
urn:nbn:se:umu:diva-198266 (URN)10.1042/BSR20220186 (DOI)000825313800001 ()35674210 (PubMedID)2-s2.0-85134083602 (Scopus ID)
Available from: 2022-08-02 Created: 2022-08-02 Last updated: 2025-02-20Bibliographically approved
Projects
WHISPER MUTATIONS [2017-01772_VR]; Umeå University
Organisations
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ORCID iD: ORCID iD iconorcid.org/0000-0003-0402-8492

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