Interplay between arginine methylation and ubiquitylation regulates KLF4-mediated genome stability and carcinogenesis

Dong Hu; Mert Gur; Zhuan Zhou; Armin Gamper; Mien Chie Hung; Naoya Fujita; Li Lan; Ivet Bahar; Yong Wan

doi:10.1038/ncomms9419

Interplay between arginine methylation and ubiquitylation regulates KLF4-mediated genome stability and carcinogenesis

Dong Hu
, Mert Gur
, Zhuan Zhou
, Armin Gamper
, Mien Chie Hung
, Naoya Fujita
, Li Lan
, Ivet Bahar
, Yong Wan^*

^*Bu çalışma için yazışmadan sorumlu yazar

University of Pittsburgh
University of Texas MD Anderson Cancer Center
China Medical University Taichung
Japanese Foundation for Cancer Research

Araştırma sonucu: Dergiye katkı › Makale › bilirkişi

131 Atıf (Scopus)

Özet

KLF4 is an important regulator of cell-fate decision, including DNA damage response and apoptosis. We identify a novel interplay between protein modifications in regulating KLF4 function. Here we show that arginine methylation of KLF4 by PRMT5 inhibits KLF4 ubiquitylation by VHL and thereby reduces KLF4 turnover, resulting in the elevation of KLF4 protein levels concomitant with increased transcription of KLF4-dependent p21 and reduced expression of KLF4-repressed Bax. Structure-based modelling and simulations provide insight into the molecular mechanisms of KLF4 recognition and catalysis by PRMT5. Following genotoxic stress, disruption of PRMT5-mediated KLF4 methylation leads to abrogation of KLF4 accumulation, which, in turn, attenuates cell cycle arrest. Mutating KLF4 methylation sites suppresses breast tumour initiation and progression, and immunohistochemical stain shows increased levels of both KLF4 and PRMT5 in breast cancer tissues. Taken together, our results point to a critical role for aberrant KLF4 regulation by PRMT5 in genome stability and breast carcinogenesis.

Orijinal dil	İngilizce
Makale numarası	8419
Dergi	Nature Communications
Hacim	6
DOI'lar	https://doi.org/10.1038/ncomms9419
Yayın durumu	Yayınlandı - 30 Eyl 2015
Harici olarak yayınlandı	Evet

Bibliyografik not

Publisher Copyright:
© 2015 Macmillan Publishers Limited. All rights reserved.

Finansman

We are grateful to Drs Wade Harper and Jianping Jin for kindly providing the TAP purification vector. We appreciate Drs Jeff Brodsky and Marc W. Kirschner for reading and discussing our manuscript. We thank Tao Cheng laboratory members for help to package lentivirus to establish stable lines. We thank Dr Xinghua Lu for helping us for bioinformatic heat map analysis. We thank Dr Sterogios Moschos for the advise on the performance of IHC analysis. We also appreciate proteomic core facilities at the Rockefeller University and the University of Pittsburgh for their service on protein identification as well as methylation analyses. This work is supported by grants CA154695, R01 GM086238, U54 HG008540-01 and 5U19AI068021-6556 from the National Institute of Health as well as National Breast Cancer Foundation, Breast Cancer Research Foundation and CPRIT RP150245.

Finansörler	Finansör numarası
National Institutes of Health
National Human Genome Research Institute	U54HG008540
Breast Cancer Research Foundation	CPRIT RP150245
National Breast Cancer Foundation

BM SKH

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10.1038/ncomms9419

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Alıntı Yap

@article{ae3ac2f9556e40f59d722ab0ba5677c5,

title = "Interplay between arginine methylation and ubiquitylation regulates KLF4-mediated genome stability and carcinogenesis",

abstract = "KLF4 is an important regulator of cell-fate decision, including DNA damage response and apoptosis. We identify a novel interplay between protein modifications in regulating KLF4 function. Here we show that arginine methylation of KLF4 by PRMT5 inhibits KLF4 ubiquitylation by VHL and thereby reduces KLF4 turnover, resulting in the elevation of KLF4 protein levels concomitant with increased transcription of KLF4-dependent p21 and reduced expression of KLF4-repressed Bax. Structure-based modelling and simulations provide insight into the molecular mechanisms of KLF4 recognition and catalysis by PRMT5. Following genotoxic stress, disruption of PRMT5-mediated KLF4 methylation leads to abrogation of KLF4 accumulation, which, in turn, attenuates cell cycle arrest. Mutating KLF4 methylation sites suppresses breast tumour initiation and progression, and immunohistochemical stain shows increased levels of both KLF4 and PRMT5 in breast cancer tissues. Taken together, our results point to a critical role for aberrant KLF4 regulation by PRMT5 in genome stability and breast carcinogenesis.",

author = "Dong Hu and Mert Gur and Zhuan Zhou and Armin Gamper and Hung, \{Mien Chie\} and Naoya Fujita and Li Lan and Ivet Bahar and Yong Wan",

year = "2015",

month = sep,

day = "30",

doi = "10.1038/ncomms9419",

language = "English",

volume = "6",

journal = "Nature Communications",

issn = "2041-1723",

publisher = "Nature Publishing Group",

}

TY - JOUR

T1 - Interplay between arginine methylation and ubiquitylation regulates KLF4-mediated genome stability and carcinogenesis

AU - Hu, Dong

AU - Gur, Mert

AU - Zhou, Zhuan

AU - Gamper, Armin

AU - Hung, Mien Chie

AU - Fujita, Naoya

AU - Lan, Li

AU - Bahar, Ivet

AU - Wan, Yong

PY - 2015/9/30

Y1 - 2015/9/30

N2 - KLF4 is an important regulator of cell-fate decision, including DNA damage response and apoptosis. We identify a novel interplay between protein modifications in regulating KLF4 function. Here we show that arginine methylation of KLF4 by PRMT5 inhibits KLF4 ubiquitylation by VHL and thereby reduces KLF4 turnover, resulting in the elevation of KLF4 protein levels concomitant with increased transcription of KLF4-dependent p21 and reduced expression of KLF4-repressed Bax. Structure-based modelling and simulations provide insight into the molecular mechanisms of KLF4 recognition and catalysis by PRMT5. Following genotoxic stress, disruption of PRMT5-mediated KLF4 methylation leads to abrogation of KLF4 accumulation, which, in turn, attenuates cell cycle arrest. Mutating KLF4 methylation sites suppresses breast tumour initiation and progression, and immunohistochemical stain shows increased levels of both KLF4 and PRMT5 in breast cancer tissues. Taken together, our results point to a critical role for aberrant KLF4 regulation by PRMT5 in genome stability and breast carcinogenesis.

AB - KLF4 is an important regulator of cell-fate decision, including DNA damage response and apoptosis. We identify a novel interplay between protein modifications in regulating KLF4 function. Here we show that arginine methylation of KLF4 by PRMT5 inhibits KLF4 ubiquitylation by VHL and thereby reduces KLF4 turnover, resulting in the elevation of KLF4 protein levels concomitant with increased transcription of KLF4-dependent p21 and reduced expression of KLF4-repressed Bax. Structure-based modelling and simulations provide insight into the molecular mechanisms of KLF4 recognition and catalysis by PRMT5. Following genotoxic stress, disruption of PRMT5-mediated KLF4 methylation leads to abrogation of KLF4 accumulation, which, in turn, attenuates cell cycle arrest. Mutating KLF4 methylation sites suppresses breast tumour initiation and progression, and immunohistochemical stain shows increased levels of both KLF4 and PRMT5 in breast cancer tissues. Taken together, our results point to a critical role for aberrant KLF4 regulation by PRMT5 in genome stability and breast carcinogenesis.

UR - https://www.scopus.com/pages/publications/84942918396

U2 - 10.1038/ncomms9419

DO - 10.1038/ncomms9419

M3 - Article

C2 - 26420673

AN - SCOPUS:84942918396

SN - 2041-1723

VL - 6

JO - Nature Communications

JF - Nature Communications

M1 - 8419

ER -

Interplay between arginine methylation and ubiquitylation regulates KLF4-mediated genome stability and carcinogenesis

Özet

Bibliyografik not

Finansman

BM SKH

Belgeye Erişim

Diğer Dosyalar ve Linkler

Parmak izi

Alıntı Yap