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Nat Commun. 2015 Sep 30;6:8419. doi: 10.1038/ncomms9419.

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

Author information

1
Department of Cell Biology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15213, USA.
2
University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania 15213, USA.
3
Department of Computational and Systems Biology, University of Pittsburgh School of Medicine, Pennsylvania 15213, USA.
4
Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
5
Center for Molecular Medicine and Graduate Institute of Cancer Biology, China Medical University, Taichung 402, Taiwan.
6
Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, Tokyo 135-8550, Japan.
7
Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Pennsylvania 15213, USA.

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.

PMID:
26420673
PMCID:
PMC4598737
DOI:
10.1038/ncomms9419
[Indexed for MEDLINE]
Free PMC Article

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