An E2F7-dependent transcriptional program modulates DNA damage repair and genomic stability

Mitxelena, Jone; Apraiz, Aintzane; Vallejo-Rodríguez, Jon; García-Santisteban, Iraia; Fullaondo, Asier; Álvarez-Fernández, Mónica; Malumbres, Marcos; Zubiaga, Ana M.

doi:10.1093/nar/gkz587

Cited by 9 publications

(5 citation statements)

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“…This is in line with our previous work, which showed that the DNA replication stress kinase Chk1 phosphorylates E2F7/8 to inhibit its transcriptional repressor function on DNA repair genes and thereby promotes DNA lesion recovery upon replication stress (Yuan et al, 2018). Moreover, two recent studies indicated that loss of E2F7 conferred resistance to DNA damaging drugs by elevating expression of DNA repair genes such as RAD51, BRIP1, and FANCE (Clements et al, 2018;Mitxelena et al, 2018). These results raise the question whether stabilization of E2F7/8 would in turn sensitize cancer cells toward chemotherapy.…”

Section: Discussionsupporting

confidence: 91%

Cyclin F‐dependent degradation of E2F7 is critical for DNA repair and G2‐phase progression

et al. 2019

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E2F7 and E2F8 act as tumor suppressors via transcriptional repression of genes involved in S‐phase entry and progression. Previously, we demonstrated that these atypical E2Fs are degraded by APC/CCdh1 during G1 phase of the cell cycle. However, the mechanism driving the downregulation of atypical E2Fs during G2 phase is unknown. Here, we show that E2F7 is targeted for degradation by the E3 ubiquitin ligase SCFcyclin F during G2. Cyclin F binds via its cyclin domain to a conserved C‐terminal CY motif on E2F7. An E2F7 mutant unable to interact with SCFcyclin F remains stable during G2. Furthermore, SCFcyclin F can also interact and induce degradation of E2F8. However, this does not require the cyclin domain of SCFcyclin F nor the CY motifs in the C‐terminus of E2F8, implying a different regulatory mechanism than for E2F7. Importantly, depletion of cyclin F causes an atypical‐E2F‐dependent delay of the G2/M transition, accompanied by reduced expression of E2F target genes involved in DNA repair. Live cell imaging of DNA damage revealed that cyclin F‐dependent regulation of atypical E2Fs is critical for efficient DNA repair and cell cycle progression.

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Section: Discussionsupporting

confidence: 91%

Cyclin F‐dependent degradation of E2F7 is critical for DNA repair and G2‐phase progression

et al. 2019

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“…In addition, further qRT-PCR and western bolt showed that E2F7 could be directly inhibited by miR-3127-5p and indirectly enhanced by LINC00284 at both the mRNA and protein levels. Recently, E2F7 has been reported to be closely related to drug resistance, cell cycle, and DNA damage repair in several cancers [32,33]. Similarly, our study also highlighted the high levels of E2F7 in PTC tissues and the relationship of its high expression with poor disease-free survival of TC patients from TCGA, while the silencing of E2F7 resulted in a decrease in PTC cell proliferation.…”

Section: Discussionsupporting

confidence: 79%

Long noncoding RNA LINC00284 facilitates cell proliferation in papillary thyroid cancer via impairing miR-3127-5p targeted E2F7 suppression

Zhou

Shao

et al. 2021

Cell Death Discov.

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Accumulating evidence has suggested that long noncoding RNAs (lncRNAs) exert crucial modulation roles in the biological behaviors of multiple malignancies. Nonetheless, the specific function of lncRNA LINC00284 in papillary thyroid cancer (PTC) remains not fully understood. The objective of this research was to explore the influence of LINC00284 in PTC and elucidate its potential mechanism. The Cancer Genome Atlas (TCGA), gene expression omnibus (GEO) datasets were used to analyze LINC00284 expression differences in thyroid cancer and normal samples, followed by the verification of qRT-PCR in our own PTC and adjacent non-tumor tissues. The impacts of LINC00284 on PTC cell growth were detected in vitro via CCK-8, colony formation, EdU assays, and in vivo via a xenograft tumor model. Bioinformatics analyses and biological experiments were conducted to illuminate the molecular mechanism. We found that LINC00284 expression was remarkably increased in PTC tissues and its overexpression was closely correlated with larger tumor size. In addition, silencing LINC00284 could effectively attenuate PTC cell proliferation, induce apoptosis and G1 arrest in vitro, as well as suppress tumorigenesis in mouse xenografts. Mechanistic investigations showed that LINC00284 acted as a competing endogenous RNA (ceRNA) for miR-3127-5p, thus resulting in the disinhibition of its endogenous target E2F7. In short, our findings indicated that LINC00284–miR-3127-5p–E2F7 axis exerted oncogenic properties in PTC and may offer a new promising target for the diagnosis and therapy of PTC.

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“…E2F7 belongs to the atypical E2F family of transcription factors and is mainly related to cell cycle arrest, DNA damage repair, and genome stability. 25 In HCC, E2F7 can promote cell cycle progression and proliferation 26 However, a recent study reported that E2F7 can suppress liver tumor growth in adult mice. 27 Therefore, the role of E2F7 in HCC is still controversial.…”

Section: Discussionmentioning

confidence: 99%

“…Thus, with models of HCC cells cultured under hypoxic conditions and HCC tissues after TACE, we identified E2F7 as a candidate gene that promotes HCC resistance to sirolimus. E2F7 belongs to the atypical E2F family of transcription factors and is mainly related to cell cycle arrest, DNA damage repair, and genome stability 25 . In HCC, E2F7 can promote cell cycle progression and proliferation through the AKT1/cyclin D1 pathway 26 .…”

Section: Discussionmentioning

confidence: 99%

E2F7 promotes mammalian target of rapamycin inhibitor resistance in hepatocellular carcinoma after liver transplantation

Ling

Zhan

Jiang

et al. 2022

American Journal of Transplantation

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The mammalian target of rapamycin (mTOR) pathway is frequently deregulated and has critical roles in cancer progression. mTOR inhibitor has been widely used in several kinds of cancers and is strongly recommended in patients with hepatocellular carcinoma (HCC) after liver transplantation (LT). However, the poor response to mTOR inhibitors due to resistance remains a challenge. Hypoxia‐associated resistance limits the therapeutic efficacy of targeted drugs. The present study established models of HCC clinical samples and cell lines resistance to mTOR inhibitor sirolimus and screened out E2F7 as a candidate gene induced by hypoxia and promoting sirolimus resistance. E2F7 suppressed mTOR complex 1 via directly binding to the promoter of the TSC1 gene and stabilizes hypoxia‐inducible factor‐1α activating its downstream genes, which are responsible for E2F7‐dependent mTOR inhibitor resistance. Clinically, low E2F7 expression could be an effective biomarker for recommending patients with HCC for anti‐mTOR–based therapies after LT. Targeting E2F7 synergistically inhibited HCC growth with sirolimus in vivo. E2F7 is a promising target to reverse mTOR inhibition resistance. Collectively, our study points to a role for E2F7 in promoting mTOR inhibitor resistance in HCC and emphasizes its potential clinical significance in patients with HCC after LT.

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An E2F7-dependent transcriptional program modulates DNA damage repair and genomic stability

Cited by 9 publications

References 0 publications

Cyclin F‐dependent degradation of E2F7 is critical for DNA repair and G2‐phase progression

Cyclin F‐dependent degradation of E2F7 is critical for DNA repair and G2‐phase progression

Long noncoding RNA LINC00284 facilitates cell proliferation in papillary thyroid cancer via impairing miR-3127-5p targeted E2F7 suppression

E2F7 promotes mammalian target of rapamycin inhibitor resistance in hepatocellular carcinoma after liver transplantation

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