Preprint Article Version 1 Preserved in Portico This version is not peer-reviewed

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

Pablo Iglesias
ORCID logo ,
Marcos Seoane
,
Irene Golán-Cancela
ORCID logo ,
Isabel Castro-Piedras
,
Máximo Fraga
,
Víctor M. Arce
,
Jose A. Costoya
* ORCID logo
Version 1 : Received: 4 September 2020 / Approved: 5 September 2020 / Online: 5 September 2020 (04:39:42 CEST)

A peer-reviewed article of this Preprint also exists.

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 (Basel). 2020 Oct 10;12(10):2907. doi: 10.3390/cancers12102907. PMID: 33050515; PMCID: PMC7599842. 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 (Basel). 2020 Oct 10;12(10):2907. doi: 10.3390/cancers12102907. PMID: 33050515; PMCID: PMC7599842.

Abstract

In recent years, poly (ADP-ribose) polymerase (PARP) inhibitors have heen evaluated for treating homologous recombination-deficient tumors, taking advantage of synthetic lethality. However, increasing evidence indicates that PARP proteins exert several cellular functions unrelated with their role on DNA repair, including function as a co-activators of transcription through protein-protein interaction with E2F1. Since the RB/E2F1 pathway is among the most frequently mutated in many tumours 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 tumors. 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. Furthermore, impairment of PARP results in a reduction of tumor growth, that is not depending of the activity of PARP on DNA repair. 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.

Keywords

Poly (ADP-Ribose) Polymerase-1; E2F1 transcription factor; cell cycle; neoplasm; glioma; animal disease models

Subject

Medicine and Pharmacology, Oncology and Oncogenics

Copyright: This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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