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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.

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. SYNOPSIS: This study reveals a novel role for KLF4 PARylation in DNA damage response in cancer, and reports a synergy between targeting KLF4 and PARP1 in the treatment of triple negative breast cancer (TNBC). PARP1 is a binding partner of KLF4 protein in response to DNA damage.Structure‐based modeling elucidates the mechanism of interaction between KLF4 and PARP1, and unveils that the YYR motif of KLF4 enables its PARylation.PARP1‐mediated PARylation of KLF4 promotes its recruitment to the chromatin, which facilitates KLF4‐mediated transcriptional function.KLF4 PARylation is required for KLF4‐mediated DNA damage response, while KLF4‐involved regulation of BRCA1‐homologous recombination (HR) is independent of PARylation.Combination of KLF4 inactivation and PARP1 blockade leads to a synergistic killing of BRCA1‐proficient TNBC tumor. [ABSTRACT FROM AUTHOR]