The E2F1 transcription factor and RB tumor suppressor moonlight as DNA repair factors

Swarnalatha, Manickavinayaham; Vélez-Cruz, Renier; Biswas, Anup; Chen, Jie; Guo, Ruifeng; Johnson, D. Gale

doi:10.1080/15384101.2020.1801190

Cited by 23 publications

(21 citation statements)

References 98 publications

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“…Emerging roles of noncanonical repair proteins, such as transcriptional regulators or zinc fingers (ZnFs), in DNA repair are particularly intriguing. For example, the multifunctional E2F1 protein, beyond its well-known role in transcription, also promotes DNA repair with its pRB partner (6,7). A growing body of literature also describes the role of ZnF proteins in maintaining genome integrity (8), including proteins acting as activators or repressors of homologous recombination (HR) repair.…”

mentioning

confidence: 99%

Zinc finger protein E4F1 cooperates with PARP-1 and BRG1 to promote DNA double-strand break repair

Moison

Chagraoui

Caron³

et al. 2021

Proc. Natl. Acad. Sci. U.S.A.

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Zinc finger (ZnF) proteins represent one of the largest families of human proteins, although most remain uncharacterized. Given that numerous ZnF proteins are able to interact with DNA and poly(ADP ribose), there is growing interest in understanding their mechanism of action in the maintenance of genome integrity. We now report that the ZnF protein E4F transcription factor 1 (E4F1) is an actor in DNA repair. Indeed, E4F1 is rapidly recruited, in a poly(ADP ribose) polymerase (PARP)-dependent manner, to DNA breaks and promotes ATR/CHK1 signaling, DNA-end resection, and subsequent homologous recombination. Moreover, we identify E4F1 as a regulator of the ATP-dependent chromatin remodeling SWI/SNF complex in DNA repair. E4F1 binds to the catalytic subunit BRG1/SMARCA4 and together with PARP-1 mediates its recruitment to DNA lesions. We also report that a proportion of human breast cancers show amplification and overexpression of E4F1 or BRG1 that are mutually exclusive with BRCA1/2 alterations. Together, these results reveal a function of E4F1 in the DNA damage response that orchestrates proper signaling and repair of double-strand breaks and document a molecular mechanism for its essential role in maintaining genome integrity and cell survival.

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confidence: 99%

Zinc finger protein E4F1 cooperates with PARP-1 and BRG1 to promote DNA double-strand break repair

Moison

Chagraoui

Caron³

et al. 2021

Proc. Natl. Acad. Sci. U.S.A.

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“…DNA damage is enhanced in cells with TRPM2 deletion after doxorubicin treatment through several mechanisms including significantly increased ROS 3 , 25 , decreased antioxidants 32 , and decreased FOXM1, E2F1, and DNA repair proteins, reported here. E2F1 regulates both expression of DNA repair genes and directly functions in DNA end resection, recruiting and retaining DNA repair factors at sites of double stranded DNA breaks and in DNA end processing 37 , 42 . FOXM1 and PLK1 regulate expression and/or function of a number of DNA damage checkpoint and repair proteins 69 .…”

Section: Discussionmentioning

confidence: 99%

“…G1/S genes are expressed through binding of activating E2F/DP complexes, when they are released from RB pocket proteins following pocket protein phosphorylation by cyclin-dependent kinases 35 . E2F1-3 transcription factors are then available to promote expression of genes controlling cell cycle S-phase entry, DNA-damage response, and mitosis 36 , 37 . G2/M genes are similarly repressed by binding of RB-like pocket proteins to DREAM complexes at specific sites, and activated by sequential binding of B-MYB-MuvB and FOXM1-MuvB complexes following phosphorylation and release of RB-like pocket proteins 35 .…”

Section: Introductionmentioning

confidence: 99%

The human ion channel TRPM2 modulates cell survival in neuroblastoma through E2F1 and FOXM1

Hirschler-Laszkiewicz

Festa

Huang

et al. 2022

Sci Rep

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Transient receptor potential channel melastatin 2 (TRPM2) is highly expressed in cancer and has an essential function in preserving viability through maintenance of mitochondrial function and antioxidant response. Here, the role of TRPM2 in cell survival was examined in neuroblastoma cells with TRPM2 deletion with CRISPR technology. Viability was significantly decreased in TRPM2 knockout after doxorubicin treatment. RNA sequence analysis and RT-qPCR revealed reduced RNAs encoding master transcription regulators FOXM1 and E2F1/2 and downstream cell cycle targets including Cyclin B1, CDK1, PLK1, and CKS1. CHIP analysis demonstrated decreased FOXM1 binding to their promoters. Western blotting confirmed decreased expression, and increased expression of CDK inhibitor p21, a CKS1 target. In cells with TRPM2 deletion, cell cycle progression to S and G2/M phases was reduced after treatment with doxorubicin. RNA sequencing also identified decreased DNA repair proteins in cells with TRPM2 deletion after doxorubicin treatment, and DNA damage was increased. Wild type TRPM2, but not Ca2+-impermeable mutant E960D, restored live cell number and reconstituted expression of E2F1, FOXM1, and cell cycle/DNA repair proteins. FOXM1 expression alone restored viability. TRPM2 is a potential therapeutic target to reduce tumor proliferation and increase doxorubicin sensitivity through modulation of FOXM1, E2F1, and cell cycle/DNA repair proteins.

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“…CDK4/6 plays a key role in cell cycle regulation. After phosphorylation, transcription factor E2F1(E2F) dissociates from retinoblastoma-associated protein (Rb) and expresses as proliferation [ 81 ]. To predict the interaction of TP53 and related ingredients of antirheumatic medicine, we performed molecular docking experiments.…”

Section: Discussionmentioning

confidence: 99%

Comparison between Heat-Clearing Medicine and Antirheumatic Medicine in Treatment of Gastric Cancer Based on Network Pharmacology, Molecular Docking, and Tumor Immune Infiltration Analysis

Kang

Wang³

et al. 2022

Evidence-Based Complementary and Alternative Medicine

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Background. Clinical research found that TCM is therapeutic in treating gastric cancer. Clearing heat is the most common method, while some antirheumatic medicines are widely used in treatment as well. To explore the pharmacological mechanism, we researched the comparison between heat-clearing medicine and antirheumatic medicine in treating gastric cancer. Methods. First, related ingredients and targets were searched, respectively, and are shown in an active ingredient-target network. Combining the relevant targets of gastric cancer, we constructed a PPI network and MCODE network. Then, GO and KEGG enrichment analyses were conducted. Molecular docking experiments were performed to verify the affinity of targets and ligands. Finally, we analyzed the tumor immune infiltration on gene expression, somatic CNA, and clinical outcome. Results. A total of 31 ingredients and 90 targets of heat-clearing medicine, 31 ingredients and 186 targets of antirheumatic medicine, and 12,155 targets of gastric cancer were collected. Antirheumatic medicine ranked the top in all the enrichment analyses. In the KEGG pathway, both types of medicines were related to pathways in cancer. In the KEGG map, AR, MMP2, ERBB2, and TP53 were the most crucial targets. Key targets and ligands were docked with low binding energy. Analysis of tumor immune infiltration showed that the expressions of AR and ERBB2 were correlated with the abundance of immune infiltration and made a difference in clinical outcomes. Conclusions. Quercetin is an important ingredient in both heat-clearing medicine and antirheumatic medicine. AR signaling pathway exists in both types of medicines. The mechanism of the antitumor effect in antirheumatic medicine was similar to trastuzumab, a targeted drug aimed at ERBB2. Both types of medicines were significant in tumor immune infiltration. The immunology of gastric tumor deserves further research.

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The E2F1 transcription factor and RB tumor suppressor moonlight as DNA repair factors

Cited by 23 publications

References 98 publications

Zinc finger protein E4F1 cooperates with PARP-1 and BRG1 to promote DNA double-strand break repair

Zinc finger protein E4F1 cooperates with PARP-1 and BRG1 to promote DNA double-strand break repair

The human ion channel TRPM2 modulates cell survival in neuroblastoma through E2F1 and FOXM1

Comparison between Heat-Clearing Medicine and Antirheumatic Medicine in Treatment of Gastric Cancer Based on Network Pharmacology, Molecular Docking, and Tumor Immune Infiltration Analysis

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