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 journalArticlepeer-review

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.

Original languageEnglish (US)
Article numbere12391
JournalEMBO Molecular Medicine
Volume12
Issue number12
DOIs
StatePublished - Dec 7 2020

Keywords

  • DNA damage response
  • DNA repair
  • KLF4
  • PARP1
  • tumorigenesis and therapeutics

ASJC Scopus subject areas

  • Molecular Medicine

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