The HSF1–PARP13–PARP1 complex facilitates DNA repair and promotes mammary tumorigenesis

Mitsuaki Fujimoto, Ryosuke Takii, Eiichi Takaki, Arpit Katiyar, Ryuichiro Nakato, Katsuhiko Shirahige and Akira Nakai ()
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Mitsuaki Fujimoto: Yamaguchi University School of Medicine
Ryosuke Takii: Yamaguchi University School of Medicine
Eiichi Takaki: Yamaguchi University School of Medicine
Arpit Katiyar: Yamaguchi University School of Medicine
Ryuichiro Nakato: Institute of Molecular and Cellular Biosciences, The University of Tokyo
Katsuhiko Shirahige: Institute of Molecular and Cellular Biosciences, The University of Tokyo
Akira Nakai: Yamaguchi University School of Medicine

Nature Communications, 2017, vol. 8, issue 1, 1-16

Abstract: Abstract Poly(ADP-ribose) polymerase 1 (PARP1) is involved in DNA repair, chromatin structure, and transcription. However, the mechanisms that regulate PARP1 distribution on DNA are poorly understood. Here, we show that heat shock transcription factor 1 (HSF1) recruits PARP1 through the scaffold protein PARP13. In response to DNA damage, activated and auto-poly-ADP-ribosylated PARP1 dissociates from HSF1–PARP13, and redistributes to DNA lesions and DNA damage-inducible gene loci. Histone deacetylase 1 maintains PARP1 in the ternary complex by inactivating PARP1 through deacetylation. Blocking ternary complex formation impairs redistribution of PARP1 during DNA damage, which reduces gene expression and DNA repair. Furthermore, ternary complex formation and PARP1 redistribution protect cells from DNA damage by promoting DNA repair, and support growth of BRCA1-null mammary tumors, which are sensitive to PARP inhibitors. Our findings identify HSF1 as a regulator of genome integrity and define this function as a guarding mechanism for a specific type of mammary tumorigenesis.

Date: 2017
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DOI: 10.1038/s41467-017-01807-7

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