BLM helicase protein negatively regulates stress granule formation through unwinding RNA G-quadruplex structures

Yehuda M. Danino; Lena Molitor; Tamar Rosenbaum-Cohen; Sebastian Kaiser; Yahel Cohen; Ziv Porat; Hagai Marmor-Kollet; Corine Katina; Alon Savidor; Ron Rotkopf; Eyal Ben-Isaac; Ofra Golani; Yishai Levin; David Monchaud; Ian D. Hickson; Eran Hornstein

doi:10.1093/nar/gkad613

BLM helicase protein negatively regulates stress granule formation through unwinding RNA G-quadruplex structures

Yehuda M. Danino, Lena Molitor, Tamar Rosenbaum-Cohen, Sebastian Kaiser, Yahel Cohen, Ziv Porat, Hagai Marmor-Kollet, Corine Katina, Alon Savidor, Ron Rotkopf, Eyal Ben-Isaac, Ofra Golani, Yishai Levin, David Monchaud, Ian D. Hickson, Eran Hornstein^*

^*Corresponding author for this work

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

3 Citations (Scopus)

Abstract

Bloom's syndrome (BLM) protein is a known nuclear helicase that is able to unwind DNA secondary structures such as G-quadruplexes (G4s). However, its role in the regulation of cytoplasmic processes that involve RNA G-quadruplexes (rG4s) has not been previously studied. Here, we demonstrate that BLM is recruited to stress granules (SGs), which are cytoplasmic biomolecular condensates composed of RNAs and RNA-binding proteins. BLM is enriched in SGs upon different stress conditions and in an rG4-dependent manner. Also, we show that BLM unwinds rG4s and acts as a negative regulator of SG formation. Altogether, our data expand the cellular activity of BLM and shed light on the function that helicases play in the dynamics of biomolecular condensates.

Original language	English
Pages (from-to)	9369-9384
Number of pages	16
Journal	Nucleic Acids Research
Volume	51
Issue number	17
Early online date	28 Jul 2023
DOIs	https://doi.org/10.1093/nar/gkad613
Publication status	Published - 22 Sept 2023

Bibliographical note

We thank members of the Hornstein group for helpful critiques, discussions, advice, and protocols. Special thanks to Welmoed van-Zuiden and Chen Bar (Weizmann) for help with iPSC-derived neurons handling, and to Emmanuel Amzallag (Weizmann) for critical reading, Jeremie Mitteaux (ICMUB) for sharing protocols, advice, and help regarding the helicase activity in vitro assay, Prof. Andrew Blackford (Oxford) that shared the RPE wt and BLM KO cells, Dr. Yosef Scolnik (Weizmann) for CD training, and Dr. Maurizio Abbate (Arivis) for technical advice and assistance in image analysis.
Funding:
E.H. is the Mondry Family Professorial Chair and Head of the Andrea L. and Lawrence A. Wolfe Family Center for Research on Neuroimmunology and Neuromodulation; research at the Hornstein laboratory is supported by the CReATe consortium and ALSA; RADALA Foundation; AFM Telethon [20 576]; Weizmann–Brazil Center for Research on Neurodegeneration at Weizmann Institute of Science; Minerva Foundation, with funding from the Federal German Ministry for Education and Research; ISF Legacy Heritage Fund [828/17]; Israel Science Foundation [135/16, 3497/21, 424/22, 425/22, 372/23]; Target ALS; ERA‐Net for Research Programs on Rare Diseases [eRARE FP7] via the Israel Ministry of Health; United States-Israel Binational Science Foundation [2 021 181]; Dr Sydney Brenner and friends; Edward and Janie Moravitz; Yeda‐Sela; Yeda‐CEO; Israel Ministry of Trade and Industry; Y. Leon Benoziyo Institute for Molecular Medicine; Nella and Leon Benoziyo Center for Neurological Diseases; Kekst Family Institute for Medical Genetics; David and Fela Shapell Family Center for Genetic Disorders Research; Crown Human Genome Center; Nathan, Shirley, Philip, and Charlene Vener New Scientist Fund; Julius and Ray Charlestein Foundation; Fraida Foundation; Wolfson Family Charitable Trust; Adelis Foundation; Merck (UK); M. Halphen; the estates of F. Sherr, L. Asseof, and L. Fulop; Goldhirsh-Yellin Foundation; Redhill Foundation–Sam and Jean Rothberg Charitable Trust; Dr Dvora and Haim Teitelbaum Endowment Fund; Supported by a research grant from the Anita James Rosen Foundation; Robert Packard Center for ALS Research at Johns Hopkins; Y.M.D. is funded by a fellowship from the CNRS-WIS center for research of RNA secondary structures; L.M. is supported by the Minerva Foundation; I.D.H. and S.K. were funded by the Danish National Research Foundation [DNRF115].

All Science Journal Classification (ASJC) codes

Genetics

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Danino, Y. M., Molitor, L., Rosenbaum-Cohen, T., Kaiser, S., Cohen, Y., Porat, Z., Marmor-Kollet, H., Katina, C., Savidor, A., Rotkopf, R., Ben-Isaac, E., Golani, O., Levin, Y., Monchaud, D., Hickson, I. D., & Hornstein, E. (2023). BLM helicase protein negatively regulates stress granule formation through unwinding RNA G-quadruplex structures. Nucleic Acids Research, 51(17), 9369-9384. https://doi.org/10.1093/nar/gkad613

@article{16abe1cafc144bd8844200f25b5dddac,

title = "BLM helicase protein negatively regulates stress granule formation through unwinding RNA G-quadruplex structures",

abstract = "Bloom's syndrome (BLM) protein is a known nuclear helicase that is able to unwind DNA secondary structures such as G-quadruplexes (G4s). However, its role in the regulation of cytoplasmic processes that involve RNA G-quadruplexes (rG4s) has not been previously studied. Here, we demonstrate that BLM is recruited to stress granules (SGs), which are cytoplasmic biomolecular condensates composed of RNAs and RNA-binding proteins. BLM is enriched in SGs upon different stress conditions and in an rG4-dependent manner. Also, we show that BLM unwinds rG4s and acts as a negative regulator of SG formation. Altogether, our data expand the cellular activity of BLM and shed light on the function that helicases play in the dynamics of biomolecular condensates.",

author = "Danino, {Yehuda M.} and Lena Molitor and Tamar Rosenbaum-Cohen and Sebastian Kaiser and Yahel Cohen and Ziv Porat and Hagai Marmor-Kollet and Corine Katina and Alon Savidor and Ron Rotkopf and Eyal Ben-Isaac and Ofra Golani and Yishai Levin and David Monchaud and Hickson, {Ian D.} and Eran Hornstein",

note = "We thank members of the Hornstein group for helpful critiques, discussions, advice, and protocols. Special thanks to Welmoed van-Zuiden and Chen Bar (Weizmann) for help with iPSC-derived neurons handling, and to Emmanuel Amzallag (Weizmann) for critical reading, Jeremie Mitteaux (ICMUB) for sharing protocols, advice, and help regarding the helicase activity in vitro assay, Prof. Andrew Blackford (Oxford) that shared the RPE wt and BLM KO cells, Dr. Yosef Scolnik (Weizmann) for CD training, and Dr. Maurizio Abbate (Arivis) for technical advice and assistance in image analysis. Funding: E.H. is the Mondry Family Professorial Chair and Head of the Andrea L. and Lawrence A. Wolfe Family Center for Research on Neuroimmunology and Neuromodulation; research at the Hornstein laboratory is supported by the CReATe consortium and ALSA; RADALA Foundation; AFM Telethon [20 576]; Weizmann–Brazil Center for Research on Neurodegeneration at Weizmann Institute of Science; Minerva Foundation, with funding from the Federal German Ministry for Education and Research; ISF Legacy Heritage Fund [828/17]; Israel Science Foundation [135/16, 3497/21, 424/22, 425/22, 372/23]; Target ALS; ERA‐Net for Research Programs on Rare Diseases [eRARE FP7] via the Israel Ministry of Health; United States-Israel Binational Science Foundation [2 021 181]; Dr Sydney Brenner and friends; Edward and Janie Moravitz; Yeda‐Sela; Yeda‐CEO; Israel Ministry of Trade and Industry; Y. Leon Benoziyo Institute for Molecular Medicine; Nella and Leon Benoziyo Center for Neurological Diseases; Kekst Family Institute for Medical Genetics; David and Fela Shapell Family Center for Genetic Disorders Research; Crown Human Genome Center; Nathan, Shirley, Philip, and Charlene Vener New Scientist Fund; Julius and Ray Charlestein Foundation; Fraida Foundation; Wolfson Family Charitable Trust; Adelis Foundation; Merck (UK); M. Halphen; the estates of F. Sherr, L. Asseof, and L. Fulop; Goldhirsh-Yellin Foundation; Redhill Foundation–Sam and Jean Rothberg Charitable Trust; Dr Dvora and Haim Teitelbaum Endowment Fund; Supported by a research grant from the Anita James Rosen Foundation; Robert Packard Center for ALS Research at Johns Hopkins; Y.M.D. is funded by a fellowship from the CNRS-WIS center for research of RNA secondary structures; L.M. is supported by the Minerva Foundation; I.D.H. and S.K. were funded by the Danish National Research Foundation [DNRF115].",

year = "2023",

month = sep,

day = "22",

doi = "10.1093/nar/gkad613",

language = "English",

volume = "51",

pages = "9369--9384",

journal = "Nucleic Acids Research",

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Danino, YM, Molitor, L, Rosenbaum-Cohen, T, Kaiser, S, Cohen, Y , Porat, Z, Marmor-Kollet, H, Katina, C, Savidor, A , Rotkopf, R, Ben-Isaac, E, Golani, O , Levin, Y, Monchaud, D, Hickson, ID & Hornstein, E 2023, 'BLM helicase protein negatively regulates stress granule formation through unwinding RNA G-quadruplex structures', Nucleic Acids Research, vol. 51, no. 17, pp. 9369-9384. https://doi.org/10.1093/nar/gkad613

TY - JOUR

T1 - BLM helicase protein negatively regulates stress granule formation through unwinding RNA G-quadruplex structures

AU - Danino, Yehuda M.

AU - Molitor, Lena

AU - Rosenbaum-Cohen, Tamar

AU - Kaiser, Sebastian

AU - Cohen, Yahel

AU - Porat, Ziv

AU - Marmor-Kollet, Hagai

AU - Katina, Corine

AU - Savidor, Alon

AU - Rotkopf, Ron

AU - Ben-Isaac, Eyal

AU - Golani, Ofra

AU - Levin, Yishai

AU - Monchaud, David

AU - Hickson, Ian D.

AU - Hornstein, Eran

N1 - We thank members of the Hornstein group for helpful critiques, discussions, advice, and protocols. Special thanks to Welmoed van-Zuiden and Chen Bar (Weizmann) for help with iPSC-derived neurons handling, and to Emmanuel Amzallag (Weizmann) for critical reading, Jeremie Mitteaux (ICMUB) for sharing protocols, advice, and help regarding the helicase activity in vitro assay, Prof. Andrew Blackford (Oxford) that shared the RPE wt and BLM KO cells, Dr. Yosef Scolnik (Weizmann) for CD training, and Dr. Maurizio Abbate (Arivis) for technical advice and assistance in image analysis. Funding: E.H. is the Mondry Family Professorial Chair and Head of the Andrea L. and Lawrence A. Wolfe Family Center for Research on Neuroimmunology and Neuromodulation; research at the Hornstein laboratory is supported by the CReATe consortium and ALSA; RADALA Foundation; AFM Telethon [20 576]; Weizmann–Brazil Center for Research on Neurodegeneration at Weizmann Institute of Science; Minerva Foundation, with funding from the Federal German Ministry for Education and Research; ISF Legacy Heritage Fund [828/17]; Israel Science Foundation [135/16, 3497/21, 424/22, 425/22, 372/23]; Target ALS; ERA‐Net for Research Programs on Rare Diseases [eRARE FP7] via the Israel Ministry of Health; United States-Israel Binational Science Foundation [2 021 181]; Dr Sydney Brenner and friends; Edward and Janie Moravitz; Yeda‐Sela; Yeda‐CEO; Israel Ministry of Trade and Industry; Y. Leon Benoziyo Institute for Molecular Medicine; Nella and Leon Benoziyo Center for Neurological Diseases; Kekst Family Institute for Medical Genetics; David and Fela Shapell Family Center for Genetic Disorders Research; Crown Human Genome Center; Nathan, Shirley, Philip, and Charlene Vener New Scientist Fund; Julius and Ray Charlestein Foundation; Fraida Foundation; Wolfson Family Charitable Trust; Adelis Foundation; Merck (UK); M. Halphen; the estates of F. Sherr, L. Asseof, and L. Fulop; Goldhirsh-Yellin Foundation; Redhill Foundation–Sam and Jean Rothberg Charitable Trust; Dr Dvora and Haim Teitelbaum Endowment Fund; Supported by a research grant from the Anita James Rosen Foundation; Robert Packard Center for ALS Research at Johns Hopkins; Y.M.D. is funded by a fellowship from the CNRS-WIS center for research of RNA secondary structures; L.M. is supported by the Minerva Foundation; I.D.H. and S.K. were funded by the Danish National Research Foundation [DNRF115].

PY - 2023/9/22

Y1 - 2023/9/22

N2 - Bloom's syndrome (BLM) protein is a known nuclear helicase that is able to unwind DNA secondary structures such as G-quadruplexes (G4s). However, its role in the regulation of cytoplasmic processes that involve RNA G-quadruplexes (rG4s) has not been previously studied. Here, we demonstrate that BLM is recruited to stress granules (SGs), which are cytoplasmic biomolecular condensates composed of RNAs and RNA-binding proteins. BLM is enriched in SGs upon different stress conditions and in an rG4-dependent manner. Also, we show that BLM unwinds rG4s and acts as a negative regulator of SG formation. Altogether, our data expand the cellular activity of BLM and shed light on the function that helicases play in the dynamics of biomolecular condensates.

AB - Bloom's syndrome (BLM) protein is a known nuclear helicase that is able to unwind DNA secondary structures such as G-quadruplexes (G4s). However, its role in the regulation of cytoplasmic processes that involve RNA G-quadruplexes (rG4s) has not been previously studied. Here, we demonstrate that BLM is recruited to stress granules (SGs), which are cytoplasmic biomolecular condensates composed of RNAs and RNA-binding proteins. BLM is enriched in SGs upon different stress conditions and in an rG4-dependent manner. Also, we show that BLM unwinds rG4s and acts as a negative regulator of SG formation. Altogether, our data expand the cellular activity of BLM and shed light on the function that helicases play in the dynamics of biomolecular condensates.

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DO - 10.1093/nar/gkad613

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AN - SCOPUS:85172122186

SN - 0305-1048

VL - 51

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EP - 9384

JO - Nucleic Acids Research

JF - Nucleic Acids Research

IS - 17

ER -

BLM helicase protein negatively regulates stress granule formation through unwinding RNA G-quadruplex structures

Abstract

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