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Selected Publications

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No country for old methods: New tools for studying microproteins

Fabiola Valdivia-FranciaAtaman Sendoel

Microproteins encoded by small open reading frames (sORFs) have emerged as a fascinating frontier in genomics. Traditionally overlooked due to their small size, recent technological advancements such as ribosome profiling, mass spectrometry-based strategies and advanced computational approaches have led to the annotation of more than 7000 sORFs in the human genome. Despite the vast progress, only a tiny portion of these microproteins have been characterized and an important challenge in the field lies in identifying functionally relevant microproteins and understanding their role in different cellular contexts. In this review, we explore the recent advancements in sORF research, focusing on the new methodologies and computational approaches that have facilitated their identification and functional characterization. Leveraging these new tools hold great promise for dissecting the diverse cellular roles of microproteins and will ultimately pave the way for understanding their role in the pathogenesis of diseases and identifying new therapeutic targets.

iScience. 2024 Jan 20;27(2):108972.doi: 10.1016/j.isci.2024.108972. eCollection 2024 Feb 16.


Exploring the pan-cancer landscape of posttranscriptional regulation

Umesh GhoshdastiderAtaman Sendoel 

Understanding the mechanisms underlying cancer gene expression is critical for precision oncology. Posttranscriptional regulation is a key determinant of protein abundance and cancer cell behavior. However, to what extent posttranscriptional regulatory mechanisms impact protein levels and cancer progression is an ongoing question. Here, we exploit cancer proteogenomics data to systematically compare mRNA-protein correlations across 14 different human cancer types. We identify two clusters of genes with particularly low mRNA-protein correlations across all cancer types, shed light on the role of posttranscriptional regulation of cancer driver genes and drug targets, and unveil a cohort of 55 mutations that alter systems-wide posttranscriptional regulation. Surprisingly, we find that decreased levels of posttranscriptional control in patients correlate with shorter overall survival across multiple cancer types, prompting further mechanistic studies into how posttranscriptional regulation affects patient outcomes. Our findings underscore the importance of a comprehensive understanding of the posttranscriptional regulatory landscape for predicting cancer progression.

Cell Rep. 2023 Oct 31;42(10):113172.doi: 10.1016/j.celrep.2023.113172. Epub 2023 Sep 25.


Monitoring the 5′UTR landscape reveals isoform switches to drive translational efficiencies in cancer

Ramona Weber  1 Umesh Ghoshdastider  1 Daniel Spies  1 Clara Duré  1   2 Fabiola Valdivia-Francia  1   2 Merima Forny  1 Mark Ormiston  1 Peter F Renz  1 David Taborsky  1   2 Merve Yigit  1   2 Martino Bernasconi  1 Homare Yamahachi  1 Ataman Sendoel  3

Transcriptional and translational control are key determinants of gene expression, however, to what extent these two processes can be collectively coordinated is still poorly understood. Here, we use Nanopore long-read sequencing and cap analysis of gene expression (CAGE-seq) to document the landscape of 5′ and 3′ untranslated region (UTR) isoforms and transcription start sites of epidermal stem cells, wild-type keratinocytes and squamous cell carcinomas. Focusing on squamous cell carcinomas, we show that a small cohort of genes with alternative 5′UTR isoforms exhibit overall increased translational efficiencies and are enriched in ribosomal proteins and splicing factors. By combining polysome fractionations and CAGE-seq, we further characterize two of these UTR isoform genes with identical coding sequences and demonstrate that the underlying transcription start site heterogeneity frequently results in 5′ terminal oligopyrimidine (TOP) and pyrimidine-rich translational element (PRTE) motif switches to drive mTORC1-dependent translation of the mRNA. Genome-wide, we show that highly translated squamous cell carcinoma transcripts switch towards increased use of 5′TOP and PRTE motifs, have generally shorter 5′UTRs and expose decreased RNA secondary structures. Notably, we found that the two 5′TOP motif-containing, but not the TOP-less, RPL21 transcript isoforms strongly correlated with overall survival in human head and neck squamous cell carcinoma patients. Our findings warrant isoform-specific analyses in human cancer datasets and suggest that switching between 5′UTR isoforms is an elegant and simple way to alter protein synthesis rates, set their sensitivity to the mTORC1-dependent nutrient-sensing pathway and direct the translational potential of an mRNA by the precise 5′UTR sequence.

Oncogene. 2023 Feb;42(9):638-650. doi: 10.1038/s41388-022-02578-2. Epub 2022 Dec 23.


Special Edition: the hidden world of non-canonical ORFs

Some like it translated: small ORFs in the 5′UTR

Peter F.Renz, Fabiola Valdivia-Francia, AtamanSendoel

The 5′ untranslated region (5′UTR) is critical in determining post-transcriptional control, which is partly mediated by short upstream open reading frames (uORFs) present in half of mammalian transcripts. uORFs are generally considered to provide functionally important repression of the main-ORF by engaging initiating ribosomes, but under specific environmental conditions such as cellular stress, uORFs can become essential to activate the translation of the main coding sequence. In addition, a growing number of uORF-encoded bioactive microproteins have been described, which have the potential to significantly increase cellular protein diversity. Here we review the diverse cellular contexts in which uORFs play a critical role and discuss the molecular mechanisms underlying their function and regulation. The progress over the last decades in dissecting uORF function suggests that the 5′UTR remains an exciting frontier towards understanding how the cellular proteome is shaped in health and disease.

Experimental Cell Research



MINA-1 and WAGO-4 are part of regulatory network coordinating germ cell death and RNAi in C. elegans.

Sendoel A, Subasic D, Ducoli L, Keller M, Michel E, Kohler I, Singh KD, Zheng X, Brümmer A, Imig J, Kishore S, Wu Y, Kanitz A, Kaech A, Mittal N, Matia-González AM, Gerber AP, Zavolan M, Aebersold R, Hall J, Allain FH, Hengartner MO.

Post-transcriptional control of mRNAs by RNA-binding proteins (RBPs) has a prominent role in the regulation of gene expression. RBPs interact with mRNAs to control their biogenesis, splicing, transport, localization, translation, and stability. Defects in such regulation can lead to a wide range of human diseases from neurological disorders to cancer. Many RBPs are conserved between Caenorhabditis elegans and humans, and several are known to regulate apoptosis in the adult C. elegans germ line. How these RBPs control apoptosis is, however, largely unknown. Here, we identify mina-1(C41G7.3) in a RNA interference-based screen as a novel regulator of apoptosis, which is exclusively expressed in the adult germ line. The absence of MINA-1 causes a dramatic increase in germ cell apoptosis, a reduction in brood size, and an impaired P granules organization and structure. In vivo crosslinking immunoprecipitation experiments revealed that MINA-1 binds a set of mRNAs coding for RBPs associated with germ cell development. Additionally, a system-wide analysis of a mina-1 deletion mutant compared with wild type, including quantitative proteome and transcriptome data, hints to a post-transcriptional regulatory RBP network driven by MINA-1 during germ cell development in C. elegans. In particular, we found that the germline-specific Argonaute WAGO-4 protein levels are increased in mina-1 mutant background. Phenotypic analysis of double mutant mina-1;wago-4 revealed that contemporary loss of MINA-1 and WAGO-4 strongly rescues the phenotypes observed in mina-1 mutant background. To strengthen this functional interaction, we found that upregulation of WAGO-4 in mina-1 mutant animals causes hypersensitivity to exogenous RNAi. Our comprehensive experimental approach allowed us to describe a phenocritical interaction between two RBPs controlling germ cell apoptosis and exogenous RNAi. These findings broaden our understanding of how RBPs can orchestrate different cellular events such as differentiation and death in C. elegans.

Cell Death Differ 2019



Translation from unconventional 5′ start sites drives tumour initiation

Ataman Sendoel, Joshua G. Dunn, Edwin H. Rodriguez, Shruti Naik, Nicholas C. Gomez, Brian Hurwitz, John Levorse, Brian D. Dill, Daniel Schramek, Henrik Molina, Jonathan S. Weissman & Elaine Fuchs.

We are just beginning to understand how translational control affects tumour initiation and malignancy. Here we use an epidermis-specific, in vivo ribosome profiling strategy to investigate the translational landscape during the transition from normal homeostasis to malignancy. Using a mouse model of inducible SOX2, which is broadly expressed in oncogenic RAS-associated cancers, we show that despite widespread reductions in translation and protein synthesis, certain oncogenic mRNAs are spared. During tumour initiation, the translational apparatus is redirected towards unconventional upstream initiation sites, enhancing the translational efficiency of oncogenic mRNAs. An in vivo RNA interference screen of translational regulators revealed that depletion of conventional eIF2 complexes has adverse effects on normal but not oncogenic growth. Conversely, the alternative initiation factor eIF2A is essential for cancer progression, during which it mediates initiation at these upstream sites, differentially skewing translation and protein expression. Our findings unveil a role for the translation of 5′ untranslated regions in cancer, and expose new targets for therapeutic intervention.

Nature Article, 2017


Unconventional translation in cancer

Translation of RNA into proteins is a fundamental process for all cells. Analysis of a mouse model of skin cancer uncovers an atypical RNA-translation program that has a vital role in tumour formation.

Nature News & Views accompanying the Nature paper.


Inflammatory memory sensitizes skin epithelial stem cells to tissue damage

Shruti Naik1*, Samantha b. Larsen1*, Nicholas c. Gomez1, Kirill Alaverdyan1, Ataman Sendoel1, Shaopeng Yuan1, Lisa Polak1, Anita Kulukian1, Sophia Chai1 & Elaine Fuchs1

The skin barrier is the body’s first line of defence against environmental assaults, and is maintained by epithelial stem cells (EpSCs). Despite the vulnerability of EpSCs to inflammatory pressures, neither the primary response to inflammation nor its enduring consequences are well understood. Here we report a prolonged memory to acute inflammation that enables mouse EpSCs to hasten barrier restoration after subsequent tissue damage. This functional adaptation does not require skin-resident macrophages or T cells. Instead, EpSCs maintain chromosomal accessibility at key stress response genes that are activated by the primary stimulus. Upon a secondary challenge, genes governed by these domains are transcribed rapidly. Fuelling this memory is Aim2, which encodes an activator of the inflammasome. The absence of AIM2 or its downstream effectors, caspase-1 and interleukin-1β, erases the ability of EpSCs to recollect inflammation. Although EpSCs benefit from inflammatory tuning by heightening their responsiveness to subsequent stressors, this enhanced sensitivity probably increases their susceptibility to autoimmune and hyperproliferative disorders, including cancer.

Nature Article, 2017


Direct in Vivo RNAi Screen Unveils Myosin IIa as a Tumor Suppressor of Squamous Cell Carcinomas

Daniel Schramek,1 Ataman Sendoel,1 Jeremy P. Segal,1* Slobodan Beronja,1 Evan Heller,1 Daniel Oristian,1 Boris Reva,2 Elaine Fuchs1†

Mining modern genomics for cancer therapies is predicated on weeding out “bystander” alterations (nonconsequential mutations) and identifying “driver” mutations responsible for tumorigenesis and/or metastasis. We used a direct in vivo RNA interference (RNAi) strategy to screen for genes that upon repression predispose mice to squamous cell carcinomas (SCCs). Seven of our top hits—including Myh9, which encodes nonmuscle myosin IIa—have not been linked to tumor development, yet tissue-specific Myh9 RNAi and Myh9 knockout trigger invasive SCC formation on tumor-susceptible backgrounds. In human and mouse keratinocytes, myosin IIa’s function is manifested not only in conventional actin-related processes but also in regulating posttranscriptional p53 stabilization. Myosin IIa is diminished in human SCCs with poor survival, which suggests that in vivo RNAi technology might be useful for identifying potent but low-penetrance tumor suppressors.

Science, 2014


DEPDC1/LET-99 participates in an evolutionarily conserved pathway for anti-tubulin drug-induced apoptosis

Ataman Sendoel1,2,6, Simona Maida3, Xue Zheng1, Youjin Teo1, Lilli Stergiou1,6, Carlo-Alberto Rossi3, Deni Subasic1, Sergio M. Pinto1, Jason M. Kinchen4, Moyin Shi1, Steffen Boettcher2, Joel N. Meyer5, Markus G. Manz2, Daniele Bano3 and Michael O. Hengartner1,7

Microtubule-targeting chemotherapeutics induce apoptosis in cancer cells by promoting the phosphorylation and degradation of the anti-apoptotic BCL-2 family member MCL1. The signalling cascade linking microtubule disruption to MCL1 degradation remains however to be defined. Here, we establish an in vivo screening strategy in Caenorhabditis elegans to uncover genes involved in chemotherapy-induced apoptosis. Using an RNAi-based screen, we identify three genes required for vincristine-induced apoptosis. We show that the DEP domain protein LET-99 acts upstream of the heterotrimeric G protein alpha subunit GPA-11 to control activation of the stress kinase JNK-1. The human homologue of LET-99, DEPDC1, similarly regulates vincristine-induced cell death by promoting JNK-dependent degradation of the BCL-2 family protein MCL1. Collectively, these data uncover an evolutionarily conserved mediator of anti-tubulin drug-induced apoptosis and suggest that DEPDC1 levels could be an additional determinant for therapy response upstream of MCL1.

Nature Cell Biology, 2014
DOI: 10.1038/ncb3010


Deficiency of FANCD2-Associated Nuclease KIAA1018/FAN1 Sensitizes Cells to Interstrand Crosslinking Agents

Katja Kratz,1,4 Barbara Schöpf,1,4 Svenja Kaden,1,4 Ataman Sendoel,2 Ralf Eberhard,2 Claudio Lademann,1 Elda Cannavo ́ ,1,5 Alessandro A. Sartori,1 Michael O. Hengartner,2 and Josef Jiricny1,3,*

Cytotoxicity of cisplatin and mitomycin C (MMC) is ascribed largely to their ability to generate inter- strand crosslinks (ICLs) in DNA, which block the progression of replication forks. The processing of ICLs requires the Fanconi anemia (FA) pathway, exci- sion repair, and translesion DNA synthesis (TLS). It also requires homologous recombination (HR), which repairs double-strand breaks (DSBs) generated by cleavage of the blocked replication forks. Here we describe KIAA1018, an evolutionarily conserved protein that has an N-terminal ubiquitin-binding zinc finger (UBZ) and a C-terminal nuclease domain. KIAA1018 is a 50/30 exonuclease and a structure- specific endonuclease that preferentially incises 50 flaps. Like cells from FA patients, human cells depleted of KIAA1018 are sensitized to ICL-inducing agents and display chromosomal instability. The link of KIAA1018 to the FA pathway is further strength- ened by its recruitment to DNA damage through interaction of its UBZ domain with monoubiquity- lated FANCD2. We therefore propose to name KIAA1018 FANCD2-associated nuclease, FAN1.

Cell, 2010
DOI 10.1016/j.cell.2010.06.022


HIF-1 antagonizes p53-mediated apoptosis through a secreted neuronal tyrosinase

Ataman Sendoel1,2,3, Ines Kohler1, Christof Fellmann1,4,5, Scott W. Lowe4,6 & Michael O. Hengartner1

Hypoxia-inducible factor (HIF) is a transcription factor that regulates fundamental cellular processes in response to changes in oxygen concentration. HIFa protein levels are increased in most solid tumours and correlate with patient prognosis. The link between HIF and apoptosis, a major determinant of cancer progression and treatment outcome, is poorly understood. Here we show that Caenorhabditis elegans HIF-1 protects against DNA-damage-induced germ cell apoptosis by antagonizing the function of CEP-1, the homologue of the tumour suppressor p53. The antiapoptotic property of HIF-1 is mediated by means of transcriptional upregulation of the tyrosinase family member TYR-2 in the ASJ sensory neurons. TYR-2 is secreted by ASJ sensory neurons to antagonize CEP-1-dependent germline apoptosis. Knock down of the TYR-2 homologue TRP2 (also called DCT) in human melanoma cells similarly increases apoptosis, indicating an evolutionarily conserved function. Our findings identify a novel link between hypoxia and programmed cell death, and provide a paradigm for HIF-1 dictating apoptotic cell fate at a distance.

Nature Article, 2010


Lack of oxygen aids cell survival

Jo Anne Powell-Coffman and Clark R. Coffman

In worms, neurons respond to low levels of environmental oxygen in a way that protects distant tissues from stress-induced cell death. The molecules that mediate this cell–cell signalling may be targets for cancer treatment.

News & Views accompanying the Nature paper.

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