A chromatin-dependent role of the fragile X mental retardation protein FMRP in the DNA damage response

Roman Alpatov; Bluma J. Lesch; Mika Nakamoto-Kinoshita; Andres Blanco; Shuzhen Chen; Alexandra Stützer; Karim J. Armache; Matthew D. Simon; Chao Xu; Muzaffar Ali; Jernej Murn; Sladjana Prisic; Tatiana G. Kutateladze; Christopher R. Vakoc; Jinrong Min; Robert E. Kingston; Wolfgang Fischle; Stephen T. Warren; David C. Page; Yang Shi

doi:10.1016/j.cell.2014.03.040

A chromatin-dependent role of the fragile X mental retardation protein FMRP in the DNA damage response

Roman Alpatov, Bluma J. Lesch, Mika Nakamoto-Kinoshita, Andres Blanco, Shuzhen Chen, Alexandra Stützer, Karim J. Armache, Matthew D. Simon, Chao Xu, Muzaffar Ali, Jernej Murn, Sladjana Prisic, Tatiana G. Kutateladze, Christopher R. Vakoc, Jinrong Min, Robert E. Kingston, Wolfgang Fischle, Stephen T. Warren, David C. Page, Yang Shi^*

^*Corresponding author for this work

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

126 Scopus citations

Abstract

Fragile X syndrome, a common form of inherited intellectual disability, is caused by loss of the fragile X mental retardation protein FMRP. FMRP is present predominantly in the cytoplasm, where it regulates translation of proteins that are important for synaptic function. We identify FMRP as a chromatin-binding protein that functions in the DNA damage response (DDR). Specifically, we show that FMRP binds chromatin through its tandem Tudor (Agenet) domain in vitro and associates with chromatin in vivo. We also demonstrate that FMRP participates in the DDR in a chromatin-binding-dependent manner. The DDR machinery is known to play important roles in developmental processes such as gametogenesis. We show that FMRP occupies meiotic chromosomes and regulates the dynamics of the DDR machinery during mouse spermatogenesis. These findings suggest that nuclear FMRP regulates genomic stability at the chromatin interface and may impact gametogenesis and some developmental aspects of fragile X syndrome.

Original language	English (US)
Pages (from-to)	869-881
Number of pages	13
Journal	Cell
Volume	157
Issue number	4
DOIs	https://doi.org/10.1016/j.cell.2014.03.040
State	Published - May 8 2014
Externally published	Yes

Bibliographical note

Funding Information:
We thank S. Elledge and B. Yankner for advice and helpful suggestions; A. Ciccia for help with DNA damage experiments; D. Reinberg and P. Voigt for help with nucleosomal preparations; J. Griesbach, A. Lazic, and S. Duhr from NanoTemper Technologies, and K. Yamagata, Y. Zheng, and X. Shang for help with microscale thermophoresis and kinetic data analysis; and E. Greer, A. Alekseyenko, and G. Shanower for logistical support. We also thank J. Mowrey, S. Ceman, S. Keeney, and U. Fischer for reagents; M. Bear for Fmr1 KO mice; S. Armstrong for Dot1L fl/fl mice; K. Luger, G. Narlikar, S. Ceman, and U. Fischer for helpful comments; and M. Goodheart, D. Cooper, E. Derby, L. Elow, K. Igarashi, L. Kolinski, L. Pomponi, and M. Schuck for technical assistance. We also thank our collaborators who contributed to this project but whose work was not included in the manuscript: B. Ren, U. Wagner, and the Ren laboratory for FMRP genome-wide analysis; K. Zhao and his group for H3K79me2 genome-wide analysis; A. Vaquero for Suv39h double-null MEFs; and G. Schotta and T. Jenuwein for Suv4-20h double null MEFs. This work was supported by NIH grants NCI118487 and MH096066 to Y.S., National Research Training Grant AG00222-7 to R.A., NRSA grant HD075591 and a Hope Funds for Cancer Research postdoctoral fellowship to B.J.L., and HHMI funding to D.C.P., and in part by NIH grants HD020521 and HD024064 to S.T.W. Y.S. is an American Cancer Society Research Professor, and is a cofounder of Constellation Pharmaceuticals and a member of its scientific advisory board.

ASJC Scopus subject areas

General Biochemistry, Genetics and Molecular Biology

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Alpatov, R., Lesch, B. J., Nakamoto-Kinoshita, M., Blanco, A., Chen, S., Stützer, A., Armache, K. J., Simon, M. D., Xu, C., Ali, M., Murn, J., Prisic, S., Kutateladze, T. G., Vakoc, C. R., Min, J., Kingston, R. E., Fischle, W., Warren, S. T., Page, D. C., & Shi, Y. (2014). A chromatin-dependent role of the fragile X mental retardation protein FMRP in the DNA damage response. Cell, 157(4), 869-881. https://doi.org/10.1016/j.cell.2014.03.040

@article{724ad5aa60fb4934a37a4ef69ea29258,

title = "A chromatin-dependent role of the fragile X mental retardation protein FMRP in the DNA damage response",

abstract = "Fragile X syndrome, a common form of inherited intellectual disability, is caused by loss of the fragile X mental retardation protein FMRP. FMRP is present predominantly in the cytoplasm, where it regulates translation of proteins that are important for synaptic function. We identify FMRP as a chromatin-binding protein that functions in the DNA damage response (DDR). Specifically, we show that FMRP binds chromatin through its tandem Tudor (Agenet) domain in vitro and associates with chromatin in vivo. We also demonstrate that FMRP participates in the DDR in a chromatin-binding-dependent manner. The DDR machinery is known to play important roles in developmental processes such as gametogenesis. We show that FMRP occupies meiotic chromosomes and regulates the dynamics of the DDR machinery during mouse spermatogenesis. These findings suggest that nuclear FMRP regulates genomic stability at the chromatin interface and may impact gametogenesis and some developmental aspects of fragile X syndrome.",

author = "Roman Alpatov and Lesch, {Bluma J.} and Mika Nakamoto-Kinoshita and Andres Blanco and Shuzhen Chen and Alexandra St{\"u}tzer and Armache, {Karim J.} and Simon, {Matthew D.} and Chao Xu and Muzaffar Ali and Jernej Murn and Sladjana Prisic and Kutateladze, {Tatiana G.} and Vakoc, {Christopher R.} and Jinrong Min and Kingston, {Robert E.} and Wolfgang Fischle and Warren, {Stephen T.} and Page, {David C.} and Yang Shi",

note = "Funding Information: We thank S. Elledge and B. Yankner for advice and helpful suggestions; A. Ciccia for help with DNA damage experiments; D. Reinberg and P. Voigt for help with nucleosomal preparations; J. Griesbach, A. Lazic, and S. Duhr from NanoTemper Technologies, and K. Yamagata, Y. Zheng, and X. Shang for help with microscale thermophoresis and kinetic data analysis; and E. Greer, A. Alekseyenko, and G. Shanower for logistical support. We also thank J. Mowrey, S. Ceman, S. Keeney, and U. Fischer for reagents; M. Bear for Fmr1 KO mice; S. Armstrong for Dot1L fl/fl mice; K. Luger, G. Narlikar, S. Ceman, and U. Fischer for helpful comments; and M. Goodheart, D. Cooper, E. Derby, L. Elow, K. Igarashi, L. Kolinski, L. Pomponi, and M. Schuck for technical assistance. We also thank our collaborators who contributed to this project but whose work was not included in the manuscript: B. Ren, U. Wagner, and the Ren laboratory for FMRP genome-wide analysis; K. Zhao and his group for H3K79me2 genome-wide analysis; A. Vaquero for Suv39h double-null MEFs; and G. Schotta and T. Jenuwein for Suv4-20h double null MEFs. This work was supported by NIH grants NCI118487 and MH096066 to Y.S., National Research Training Grant AG00222-7 to R.A., NRSA grant HD075591 and a Hope Funds for Cancer Research postdoctoral fellowship to B.J.L., and HHMI funding to D.C.P., and in part by NIH grants HD020521 and HD024064 to S.T.W. Y.S. is an American Cancer Society Research Professor, and is a cofounder of Constellation Pharmaceuticals and a member of its scientific advisory board. ",

year = "2014",

month = may,

day = "8",

doi = "10.1016/j.cell.2014.03.040",

language = "English (US)",

volume = "157",

pages = "869--881",

journal = "Cell",

issn = "0092-8674",

publisher = "Elsevier B.V.",

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Alpatov, R, Lesch, BJ, Nakamoto-Kinoshita, M, Blanco, A, Chen, S, Stützer, A, Armache, KJ, Simon, MD, Xu, C, Ali, M, Murn, J, Prisic, S, Kutateladze, TG, Vakoc, CR, Min, J, Kingston, RE, Fischle, W, Warren, ST, Page, DC & Shi, Y 2014, 'A chromatin-dependent role of the fragile X mental retardation protein FMRP in the DNA damage response', Cell, vol. 157, no. 4, pp. 869-881. https://doi.org/10.1016/j.cell.2014.03.040

TY - JOUR

T1 - A chromatin-dependent role of the fragile X mental retardation protein FMRP in the DNA damage response

AU - Alpatov, Roman

AU - Lesch, Bluma J.

AU - Nakamoto-Kinoshita, Mika

AU - Blanco, Andres

AU - Chen, Shuzhen

AU - Stützer, Alexandra

AU - Armache, Karim J.

AU - Simon, Matthew D.

AU - Xu, Chao

AU - Ali, Muzaffar

AU - Murn, Jernej

AU - Prisic, Sladjana

AU - Kutateladze, Tatiana G.

AU - Vakoc, Christopher R.

AU - Min, Jinrong

AU - Kingston, Robert E.

AU - Fischle, Wolfgang

AU - Warren, Stephen T.

AU - Page, David C.

AU - Shi, Yang

N1 - Funding Information: We thank S. Elledge and B. Yankner for advice and helpful suggestions; A. Ciccia for help with DNA damage experiments; D. Reinberg and P. Voigt for help with nucleosomal preparations; J. Griesbach, A. Lazic, and S. Duhr from NanoTemper Technologies, and K. Yamagata, Y. Zheng, and X. Shang for help with microscale thermophoresis and kinetic data analysis; and E. Greer, A. Alekseyenko, and G. Shanower for logistical support. We also thank J. Mowrey, S. Ceman, S. Keeney, and U. Fischer for reagents; M. Bear for Fmr1 KO mice; S. Armstrong for Dot1L fl/fl mice; K. Luger, G. Narlikar, S. Ceman, and U. Fischer for helpful comments; and M. Goodheart, D. Cooper, E. Derby, L. Elow, K. Igarashi, L. Kolinski, L. Pomponi, and M. Schuck for technical assistance. We also thank our collaborators who contributed to this project but whose work was not included in the manuscript: B. Ren, U. Wagner, and the Ren laboratory for FMRP genome-wide analysis; K. Zhao and his group for H3K79me2 genome-wide analysis; A. Vaquero for Suv39h double-null MEFs; and G. Schotta and T. Jenuwein for Suv4-20h double null MEFs. This work was supported by NIH grants NCI118487 and MH096066 to Y.S., National Research Training Grant AG00222-7 to R.A., NRSA grant HD075591 and a Hope Funds for Cancer Research postdoctoral fellowship to B.J.L., and HHMI funding to D.C.P., and in part by NIH grants HD020521 and HD024064 to S.T.W. Y.S. is an American Cancer Society Research Professor, and is a cofounder of Constellation Pharmaceuticals and a member of its scientific advisory board.

PY - 2014/5/8

Y1 - 2014/5/8

N2 - Fragile X syndrome, a common form of inherited intellectual disability, is caused by loss of the fragile X mental retardation protein FMRP. FMRP is present predominantly in the cytoplasm, where it regulates translation of proteins that are important for synaptic function. We identify FMRP as a chromatin-binding protein that functions in the DNA damage response (DDR). Specifically, we show that FMRP binds chromatin through its tandem Tudor (Agenet) domain in vitro and associates with chromatin in vivo. We also demonstrate that FMRP participates in the DDR in a chromatin-binding-dependent manner. The DDR machinery is known to play important roles in developmental processes such as gametogenesis. We show that FMRP occupies meiotic chromosomes and regulates the dynamics of the DDR machinery during mouse spermatogenesis. These findings suggest that nuclear FMRP regulates genomic stability at the chromatin interface and may impact gametogenesis and some developmental aspects of fragile X syndrome.

AB - Fragile X syndrome, a common form of inherited intellectual disability, is caused by loss of the fragile X mental retardation protein FMRP. FMRP is present predominantly in the cytoplasm, where it regulates translation of proteins that are important for synaptic function. We identify FMRP as a chromatin-binding protein that functions in the DNA damage response (DDR). Specifically, we show that FMRP binds chromatin through its tandem Tudor (Agenet) domain in vitro and associates with chromatin in vivo. We also demonstrate that FMRP participates in the DDR in a chromatin-binding-dependent manner. The DDR machinery is known to play important roles in developmental processes such as gametogenesis. We show that FMRP occupies meiotic chromosomes and regulates the dynamics of the DDR machinery during mouse spermatogenesis. These findings suggest that nuclear FMRP regulates genomic stability at the chromatin interface and may impact gametogenesis and some developmental aspects of fragile X syndrome.

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DO - 10.1016/j.cell.2014.03.040

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AN - SCOPUS:84900333592

SN - 0092-8674

VL - 157

SP - 869

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JO - Cell

JF - Cell

IS - 4

ER -

A chromatin-dependent role of the fragile X mental retardation protein FMRP in the DNA damage response

Abstract

Bibliographical note

ASJC Scopus subject areas

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