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.
Highlights
Poly(ADP-ribose) polymerase 1 (PARP1) is involved in DNA repair, chromatin structure, and transcription
Because PARP13, which is known as zinc finger antiviral protein (ZAP or ZC3HAV), was shown previously to be a human heat shock transcription factor 1 (HSF1)-interacting protein[32], we examined the interaction of hHSF1 with human PARPs including DNAdependent PARPs (PARP1, 2), and RNA-binding CCCH-PARPs (PARP7, 12, 13)[33]
The primary function of HSF1 is to maintain the proteome balance in a cell by inducing HSPs and non-HSP proteins involved in protein degradation, and loss of HSF1 activity is closely associated with the progression of aging and age-related neurodegenerative diseases[17]
Summary
Poly(ADP-ribose) polymerase 1 (PARP1) is involved in DNA repair, chromatin structure, and transcription. Blocking ternary complex formation impairs redistribution of PARP1 during DNA damage, which reduces gene expression and DNA repair. In order to cope with a variety of environmental and metabolic perturbations, cells have evolved sophisticated surveillance mechanisms including the DNA damage response (DDR) pathway to repair lesions in the DNA and facilitate replication[1, 2]. DDR proteins have an impact on a variety of cellular processes including DNA repair, chromatin remodeling, transcription, and cell cycle checkpoint. PARP1 regulates transcription of inducible genes in response to stimuli such as heat shock and hormone treatment through poly(ADP-ribose) (PAR) modification of histones[10,11,12,13,14]. HSF1 mostly remains as an inert monomer in unstressed cells, and is converted to an active trimer that binds to the heat shock response element (HSE) and robustly induces the expression of HSPs during heat shock[20,21,22]
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