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PARP1 Deficiency Reduces Tumour Growth by Decreasing E2F1 Hyperactivation: A Novel Mechanism in the Treatment of Cancer

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Molecular Oncology Laboratory MOL, Departamento de Fisioloxía, Centro Singular de Investigación en Medicina Molecular e Enfermidades Crónicas (CiMUS), Facultade de Medicina, Universidade de Santiago de Compostela, Instituto de Investigación Sanitaria de Santiago de Compostela (IDIS), 15782 Santiago de Compostela, Spain
2
Departamento de Anatomía Patolóxica e Ciencias Forenses, Universidade de Santiago de Compostela, 15782 Santiago de Compostela, Spain
*
Author to whom correspondence should be addressed.
Cancers 2020, 12(10), 2907; https://doi.org/10.3390/cancers12102907
Received: 4 September 2020 / Revised: 1 October 2020 / Accepted: 3 October 2020 / Published: 10 October 2020
PARP1 is one of the best characterized enzymes in DNA repair and an attractive target for drug design in cancer therapies. Beyond repair, PARP1 modulates the activity of several transcription factors, of which E2F1 stands out given its critical role in cell cycle regulation. Here, we show that the aberrant activation of E2F1 found in several types of cancer can be alleviated by inactivating PARP1. We believe our findings show the potential of designing novel protein-protein disruptors able to reduce the oncogenic activity of E2F1.
In recent years, poly (ADP-ribose) polymerase (PARP) inhibitors have been evaluated for treating homologous recombination-deficient tumours, taking advantage of synthetic lethality. However, increasing evidence indicates that PARP1 exert several cellular functions unrelated with their role on DNA repair, including function as a co-activator of transcription through protein-protein interaction with E2F1. Since the RB/E2F1 pathway is among the most frequently mutated in many tumour types, we investigated whether the absence of PARP activity could counteract the consequences of E2F1 hyperactivation. Our results demonstrate that genetic ablation of Parp1 extends the survival of Rb-null embryos, while genetic inactivation of Parp1 results in reduced development of pRb-dependent tumours. Our results demonstrate that PARP1 plays a key role as a transcriptional co-activator of the transcription factor E2F1, an important component of the cell cycle regulation. Considering that most oncogenic processes are associated with cell cycle deregulation, the disruption of this PARP1-E2F1 interaction could provide a new therapeutic target of great interest and a wide spectrum of indications. View Full-Text
Keywords: Poly (ADP-Ribose) Polymerase-1; E2F1 transcription factor; cell cycle; neoplasm; glioma; animal disease models Poly (ADP-Ribose) Polymerase-1; E2F1 transcription factor; cell cycle; neoplasm; glioma; animal disease models
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MDPI and ACS Style

Iglesias, P.; Seoane, M.; Golán, I.; Castro-Piedras, I.; Fraga, M.; Arce, V.M.; Costoya, J.A. PARP1 Deficiency Reduces Tumour Growth by Decreasing E2F1 Hyperactivation: A Novel Mechanism in the Treatment of Cancer. Cancers 2020, 12, 2907. https://doi.org/10.3390/cancers12102907

AMA Style

Iglesias P, Seoane M, Golán I, Castro-Piedras I, Fraga M, Arce VM, Costoya JA. PARP1 Deficiency Reduces Tumour Growth by Decreasing E2F1 Hyperactivation: A Novel Mechanism in the Treatment of Cancer. Cancers. 2020; 12(10):2907. https://doi.org/10.3390/cancers12102907

Chicago/Turabian Style

Iglesias, Pablo; Seoane, Marcos; Golán, Irene; Castro-Piedras, Isabel; Fraga, Máximo; Arce, Víctor M.; Costoya, Jose A. 2020. "PARP1 Deficiency Reduces Tumour Growth by Decreasing E2F1 Hyperactivation: A Novel Mechanism in the Treatment of Cancer" Cancers 12, no. 10: 2907. https://doi.org/10.3390/cancers12102907

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