New insight into the significance of KLF4 PARylation in genome stability, carcinogenesis, and therapy

Zhuan Zhou; Furong Huang; Indira Shrivastava; Rui Zhu; Aiping Luo; Michael Hottiger; Ivet Bahar; Zhihua Liu; Massimo Cristofanilli; Yong Wan

doi:10.15252/emmm.202012391

New insight into the significance of KLF4 PARylation in genome stability, carcinogenesis, and therapy

Zhuan Zhou, Furong Huang, Indira Shrivastava, Rui Zhu, Aiping Luo, Michael Hottiger, Ivet Bahar, Zhihua Liu, Massimo Cristofanilli, Yong Wan^*

^*Corresponding author for this work

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

11 Scopus citations

Abstract

KLF4 plays a critical role in determining cell fate responding to various stresses or oncogenic signaling. Here, we demonstrated that KLF4 is tightly regulated by poly(ADP-ribosyl)ation (PARylation). We revealed the subcellular compartmentation for KLF4 is orchestrated by PARP1-mediated PARylation. We identified that PARylation of KLF4 is critical to govern KLF4 transcriptional activity through recruiting KLF4 from soluble nucleus to the chromatin. We mapped molecular motifs on KLF4 and PARP1 that facilitate their interaction and unveiled the pivotal role of the PBZ domain YYR motif (Y430, Y451 and R452) on KLF4 in enabling PARP1-mediated PARylation of KLF4. Disruption of KLF4 PARylation results in failure in DNA damage response. Depletion of KLF4 by RNA interference or interference with PARP1 function by KLF4^YYR/AAA (a PARylation-deficient mutant) significantly sensitizes breast cancer cells to PARP inhibitors. We further demonstrated the role of KLF4 in modulating homologous recombination through regulating BRCA1 transcription. Our work points to the synergism between KLF4 and PARP1 in tumorigenesis and cancer therapy, which provides a potential new therapeutic strategy for killing BRCA1-proficient triple-negative breast cancer cells.

Original language	English (US)
Article number	e12391
Journal	EMBO Molecular Medicine
Volume	12
Issue number	12
DOIs	https://doi.org/10.15252/emmm.202012391
State	Published - Dec 7 2020

Funding

We are grateful to Drs. Wade Harper and Jianping Jin for kindly providing the TAP purification vector. We appreciate Dr. Engda Hagos for providing KLF4 MEF cells. We thank Dr. Lan Li for sharing with us the PARP MEF cells as well as HR and NHEJ assay systems. We appreciate the Proteomics Core at the University of Pittsburgh for mass spectrometry analyses. We thank all members of Wan, Liu, and Bahar laboratories for their helpful comments and discussion. This work was supported by the Northwestern University Zell scholar fund, and effort for YW is covered by NIH R01CA250110, R01CA154695, and R01CA202963. Support from NIH grants U54 HG008540 and P41 GM103712 is gratefully acknowledged by IB. Support from National Nature Science Foundation of China (81130043) is acknowledged by ZL. −/− −/−

Keywords

DNA damage response
DNA repair
KLF4
PARP1
tumorigenesis and therapeutics

ASJC Scopus subject areas

Molecular Medicine

UN SDGs

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

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10.15252/emmm.202012391

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title = "New insight into the significance of KLF4 PARylation in genome stability, carcinogenesis, and therapy",

abstract = "KLF4 plays a critical role in determining cell fate responding to various stresses or oncogenic signaling. Here, we demonstrated that KLF4 is tightly regulated by poly(ADP-ribosyl)ation (PARylation). We revealed the subcellular compartmentation for KLF4 is orchestrated by PARP1-mediated PARylation. We identified that PARylation of KLF4 is critical to govern KLF4 transcriptional activity through recruiting KLF4 from soluble nucleus to the chromatin. We mapped molecular motifs on KLF4 and PARP1 that facilitate their interaction and unveiled the pivotal role of the PBZ domain YYR motif (Y430, Y451 and R452) on KLF4 in enabling PARP1-mediated PARylation of KLF4. Disruption of KLF4 PARylation results in failure in DNA damage response. Depletion of KLF4 by RNA interference or interference with PARP1 function by KLF4YYR/AAA (a PARylation-deficient mutant) significantly sensitizes breast cancer cells to PARP inhibitors. We further demonstrated the role of KLF4 in modulating homologous recombination through regulating BRCA1 transcription. Our work points to the synergism between KLF4 and PARP1 in tumorigenesis and cancer therapy, which provides a potential new therapeutic strategy for killing BRCA1-proficient triple-negative breast cancer cells.",

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AU - Hottiger, Michael

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New insight into the significance of KLF4 PARylation in genome stability, carcinogenesis, and therapy

Abstract

Funding

Keywords

ASJC Scopus subject areas

UN SDGs

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