NANOS2 is a sequence-specific mRNA-binding protein that promotes transcript degradation in spermatogonial stem cells

Azzurra Codino; Tomasz Turowski; Louie N van de Lagemaat; Ivayla Ivanova; Andrea Tavosanis; Christian Much; Tania Auchynnikava; Lina Vasiliauskaitė; Marcos Morgan; Juri Rappsilber; Robin C Allshire; Kamil R Kranc; David Tollervey; Dónal O'Carroll

doi:10.1016/j.isci.2021.102762

NANOS2 is a sequence-specific mRNA-binding protein that promotes transcript degradation in spermatogonial stem cells

Azzurra Codino, Tomasz Turowski, Louie N van de Lagemaat, Ivayla Ivanova, Andrea Tavosanis, Christian Much, Tania Auchynnikava, Lina Vasiliauskaitė, Marcos Morgan, Juri Rappsilber, Robin C Allshire, Kamil R Kranc, David Tollervey, Dónal O'Carroll^* (Corresponding Author)

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

8 Citations (Scopus)

Abstract

Spermatogonial stem cells (SSCs) sustain spermatogenesis and fertility throughout adult male life. The conserved RNA-binding protein NANOS2 is essential for the maintenance of SSCs, but its targets and mechanisms of function are not fully understood. Here, we generated a fully functional epitope-tagged Nanos2 mouse allele and applied the highly stringent cross-linking and analysis of cDNAs to define NANOS2 RNA occupancy in SSC lines. NANOS2 recognizes the AUKAAWU consensus motif, mostly found in the 3' untranslated region of defined messenger RNAs (mRNAs). We find that NANOS2 is a regulator of key signaling and metabolic pathways whose dosage or activity are known to be critical for SSC maintenance. NANOS2 interacts with components of CCR4-NOT deadenylase complex in SSC lines, and consequently, NANOS2 binding reduces the half-lives of target transcripts. In summary, NANOS2 contributes to SSC maintenance through the regulation of target mRNA stability and key self-renewal pathways.

Original language	English
Pages (from-to)	102762
Number of pages	20
Journal	iScience
Volume	24
Issue number	7
Early online date	6 Jul 2021
DOIs	https://doi.org/10.1016/j.isci.2021.102762
Publication status	Published - 23 Jul 2021
Externally published	Yes

Bibliographical note

This research was supported by the Wellcome Trust funding to DOC (106144), DT (077248), JR (103139), RCA (095021, 200885), the Wellcome Center for Cell Biology (203149) and a multi-user equipment grant [108504]. TWT was supported by the Polish Ministry of Science and Higher Education Mobility Plus program (1069/MOB/2013/0). K.R.K.’s laboratory is supported by Cancer Research UK (CRUK) Senior Cancer Research Fellowship, a CRUK Program Grant (awards C29967/A14633 and C29967/A26787), and Bloodwise and MRC project grants. We acknowledge the services of the CRM FACS and microscopy facilities as well as the EMBL Heidelberg GeneCore and Protein Purification facilities.

Data Availability Statement

Data and code availability
The CRAC, RNA-seq, and SLAM-seq data sets generated in this study are available at GEO, accession GSE149835. The data supporting this study are available in the supplementary information.

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.isci.2021.102762Licence: CC BY

Codino_etal_iSci_NANOS2_is_a_VOR
ª 2021 The Author(s). This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
Final published version, 2.48 MBLicence: CC BY

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Codino, A., Turowski, T., van de Lagemaat, L. N., Ivanova, I., Tavosanis, A., Much, C., Auchynnikava, T., Vasiliauskaitė, L., Morgan, M., Rappsilber, J., Allshire, R. C., Kranc, K. R., Tollervey, D., & O'Carroll, D. (2021). NANOS2 is a sequence-specific mRNA-binding protein that promotes transcript degradation in spermatogonial stem cells. iScience, 24(7), 102762. https://doi.org/10.1016/j.isci.2021.102762

Codino, A, Turowski, T, van de Lagemaat, LN, Ivanova, I, Tavosanis, A, Much, C, Auchynnikava, T, Vasiliauskaitė, L, Morgan, M, Rappsilber, J, Allshire, RC, Kranc, KR, Tollervey, D & O'Carroll, D 2021, 'NANOS2 is a sequence-specific mRNA-binding protein that promotes transcript degradation in spermatogonial stem cells', iScience, vol. 24, no. 7, pp. 102762. https://doi.org/10.1016/j.isci.2021.102762

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title = "NANOS2 is a sequence-specific mRNA-binding protein that promotes transcript degradation in spermatogonial stem cells",

abstract = "Spermatogonial stem cells (SSCs) sustain spermatogenesis and fertility throughout adult male life. The conserved RNA-binding protein NANOS2 is essential for the maintenance of SSCs, but its targets and mechanisms of function are not fully understood. Here, we generated a fully functional epitope-tagged Nanos2 mouse allele and applied the highly stringent cross-linking and analysis of cDNAs to define NANOS2 RNA occupancy in SSC lines. NANOS2 recognizes the AUKAAWU consensus motif, mostly found in the 3' untranslated region of defined messenger RNAs (mRNAs). We find that NANOS2 is a regulator of key signaling and metabolic pathways whose dosage or activity are known to be critical for SSC maintenance. NANOS2 interacts with components of CCR4-NOT deadenylase complex in SSC lines, and consequently, NANOS2 binding reduces the half-lives of target transcripts. In summary, NANOS2 contributes to SSC maintenance through the regulation of target mRNA stability and key self-renewal pathways.",

author = "Azzurra Codino and Tomasz Turowski and {van de Lagemaat}, {Louie N} and Ivayla Ivanova and Andrea Tavosanis and Christian Much and Tania Auchynnikava and Lina Vasiliauskaitė and Marcos Morgan and Juri Rappsilber and Allshire, {Robin C} and Kranc, {Kamil R} and David Tollervey and D{\'o}nal O'Carroll",

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AU - Ivanova, Ivayla

AU - Tavosanis, Andrea

AU - Much, Christian

AU - Auchynnikava, Tania

AU - Vasiliauskaitė, Lina

AU - Morgan, Marcos

AU - Rappsilber, Juri

AU - Allshire, Robin C

AU - Kranc, Kamil R

AU - Tollervey, David

AU - O'Carroll, Dónal

N1 - This research was supported by the Wellcome Trust funding to DOC (106144), DT (077248), JR (103139), RCA (095021, 200885), the Wellcome Center for Cell Biology (203149) and a multi-user equipment grant [108504]. TWT was supported by the Polish Ministry of Science and Higher Education Mobility Plus program (1069/MOB/2013/0). K.R.K.’s laboratory is supported by Cancer Research UK (CRUK) Senior Cancer Research Fellowship, a CRUK Program Grant (awards C29967/A14633 and C29967/A26787), and Bloodwise and MRC project grants. We acknowledge the services of the CRM FACS and microscopy facilities as well as the EMBL Heidelberg GeneCore and Protein Purification facilities.

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N2 - Spermatogonial stem cells (SSCs) sustain spermatogenesis and fertility throughout adult male life. The conserved RNA-binding protein NANOS2 is essential for the maintenance of SSCs, but its targets and mechanisms of function are not fully understood. Here, we generated a fully functional epitope-tagged Nanos2 mouse allele and applied the highly stringent cross-linking and analysis of cDNAs to define NANOS2 RNA occupancy in SSC lines. NANOS2 recognizes the AUKAAWU consensus motif, mostly found in the 3' untranslated region of defined messenger RNAs (mRNAs). We find that NANOS2 is a regulator of key signaling and metabolic pathways whose dosage or activity are known to be critical for SSC maintenance. NANOS2 interacts with components of CCR4-NOT deadenylase complex in SSC lines, and consequently, NANOS2 binding reduces the half-lives of target transcripts. In summary, NANOS2 contributes to SSC maintenance through the regulation of target mRNA stability and key self-renewal pathways.

AB - Spermatogonial stem cells (SSCs) sustain spermatogenesis and fertility throughout adult male life. The conserved RNA-binding protein NANOS2 is essential for the maintenance of SSCs, but its targets and mechanisms of function are not fully understood. Here, we generated a fully functional epitope-tagged Nanos2 mouse allele and applied the highly stringent cross-linking and analysis of cDNAs to define NANOS2 RNA occupancy in SSC lines. NANOS2 recognizes the AUKAAWU consensus motif, mostly found in the 3' untranslated region of defined messenger RNAs (mRNAs). We find that NANOS2 is a regulator of key signaling and metabolic pathways whose dosage or activity are known to be critical for SSC maintenance. NANOS2 interacts with components of CCR4-NOT deadenylase complex in SSC lines, and consequently, NANOS2 binding reduces the half-lives of target transcripts. In summary, NANOS2 contributes to SSC maintenance through the regulation of target mRNA stability and key self-renewal pathways.

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NANOS2 is a sequence-specific mRNA-binding protein that promotes transcript degradation in spermatogonial stem cells

Abstract

Bibliographical note

Data Availability Statement

UN SDGs

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