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 PAR...
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| Format: | Article |
| Language: | English |
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Springer Nature
2020-12-01
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| Series: | EMBO Molecular Medicine |
| Subjects: | |
| Online Access: | https://doi.org/10.15252/emmm.202012391 |
| _version_ | 1797285602898477056 |
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| author | Zhuan Zhou Furong Huang Indira Shrivastava Rui Zhu Aiping Luo Michael Hottiger Ivet Bahar Zhihua Liu Massimo Cristofanilli Yong Wan |
| author_facet | Zhuan Zhou Furong Huang Indira Shrivastava Rui Zhu Aiping Luo Michael Hottiger Ivet Bahar Zhihua Liu Massimo Cristofanilli Yong Wan |
| author_sort | Zhuan Zhou |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-07T18:05:34Z |
| format | Article |
| id | doaj.art-687e65add3b54ce99a500eeaf7575523 |
| institution | Directory Open Access Journal |
| issn | 1757-4676 1757-4684 |
| language | English |
| last_indexed | 2024-03-07T18:05:34Z |
| publishDate | 2020-12-01 |
| publisher | Springer Nature |
| record_format | Article |
| series | EMBO Molecular Medicine |
| spelling | doaj.art-687e65add3b54ce99a500eeaf75755232024-03-02T09:24:54ZengSpringer NatureEMBO Molecular Medicine1757-46761757-46842020-12-011212n/an/a10.15252/emmm.202012391New insight into the significance of KLF4 PARylation in genome stability, carcinogenesis, and therapyZhuan Zhou0Furong Huang1Indira Shrivastava2Rui Zhu3Aiping Luo4Michael Hottiger5Ivet Bahar6Zhihua Liu7Massimo Cristofanilli8Yong Wan9Department of Obstetrics and Gynecology Department of Pharmacology The Robert H. Lurie Comprehensive Cancer Center Northwestern University Feinberg School of Medicine Chicago IL USAState Key Laboratory of Molecular Oncology National Cancer Center/National Clinical Research Center for Cancer/Cancer HospitalChinese Academy of Medical Sciences and Peking Union Medical College Beijing ChinaDepartment of Computational and Systems Biology University of Pittsburgh School of Medicine Pittsburgh PA USAState Key Laboratory of Molecular Oncology National Cancer Center/National Clinical Research Center for Cancer/Cancer HospitalChinese Academy of Medical Sciences and Peking Union Medical College Beijing ChinaState Key Laboratory of Molecular Oncology National Cancer Center/National Clinical Research Center for Cancer/Cancer HospitalChinese Academy of Medical Sciences and Peking Union Medical College Beijing ChinaDepartment of Molecular Mechanisms of Disease University of Zurich Zurich SwitzerlandDepartment of Computational and Systems Biology University of Pittsburgh School of Medicine Pittsburgh PA USAState Key Laboratory of Molecular Oncology National Cancer Center/National Clinical Research Center for Cancer/Cancer HospitalChinese Academy of Medical Sciences and Peking Union Medical College Beijing ChinaLynn Sage Breast Cancer Program Department of Medicine‐Hematology and Oncology Robert H. Lurie Comprehensive Cancer Center Northwestern University Feinberg School of Medicine Chicago IL USADepartment of Obstetrics and Gynecology Department of Pharmacology The Robert H. Lurie Comprehensive Cancer Center Northwestern University Feinberg School of Medicine Chicago IL USAAbstract 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.https://doi.org/10.15252/emmm.202012391DNA damage responseDNA repairKLF4PARP1tumorigenesis and therapeutics |
| spellingShingle | Zhuan Zhou Furong Huang Indira Shrivastava Rui Zhu Aiping Luo Michael Hottiger Ivet Bahar Zhihua Liu Massimo Cristofanilli Yong Wan New insight into the significance of KLF4 PARylation in genome stability, carcinogenesis, and therapy EMBO Molecular Medicine DNA damage response DNA repair KLF4 PARP1 tumorigenesis and therapeutics |
| title | New insight into the significance of KLF4 PARylation in genome stability, carcinogenesis, and therapy |
| title_full | New insight into the significance of KLF4 PARylation in genome stability, carcinogenesis, and therapy |
| title_fullStr | New insight into the significance of KLF4 PARylation in genome stability, carcinogenesis, and therapy |
| title_full_unstemmed | New insight into the significance of KLF4 PARylation in genome stability, carcinogenesis, and therapy |
| title_short | New insight into the significance of KLF4 PARylation in genome stability, carcinogenesis, and therapy |
| title_sort | new insight into the significance of klf4 parylation in genome stability carcinogenesis and therapy |
| topic | DNA damage response DNA repair KLF4 PARP1 tumorigenesis and therapeutics |
| url | https://doi.org/10.15252/emmm.202012391 |
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