Transcription-Replication Conflicts: Orientation Matters

Lin, Yi-Ching; Pasero, Philippe

doi:10.1016/j.cell.2017.07.040

Cited by 14 publications

(17 citation statements)

References 10 publications

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“…S5 B and C). We thus conclude that the E2-induced γH2AX foci seen in G 1 phase do not result from transcriptional elongation or the resulting R-loop formation (31,(34)(35)(36). The data suggest that E2induced γH2AX foci may represent TOP2ccs formed at transcriptional regulatory sequences such as the promoter (10, 37, 38).…”

Section: Loss Of Brca1 Causes Prolonged γH2ax-focus Formation After Pmentioning

confidence: 77%

“…Collision between pathological TOP2ccs and replication forks may result in the collapse of replication forks. In addition to this TOP2-dependent genotoxicity, collision between E2-induced R loops and replication forks could cause DSBs in the S phase of BRCA1-deficient cells, since the formation of the R loops is suppressed by BRCA1 (31,(34)(35)(36). These collision events may lead to the formation of the DSBs that are repaired by BRCA1-mediated HDR.…”

Section: Discussionmentioning

confidence: 99%

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BRCA1 ensures genome integrity by eliminating estrogen-induced pathological topoisomerase II–DNA complexes

Sasanuma

Tsuda

Morimoto

et al. 2018

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

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Women having BRCA1 germ-line mutations develop cancer in breast and ovary, estrogen-regulated tissues, with high penetrance. Binding of estrogens to the estrogen receptor (ER) transiently induces DNA double-strand breaks (DSBs) by topoisomerase II (TOP2) and controls gene transcription. TOP2 resolves catenated DNA by transiently generating DSBs, TOP2-cleavage complexes (TOP2ccs), where TOP2 covalently binds to 5′ ends of DSBs. TOP2 frequently fails to complete its catalysis, leading to formation of pathological TOP2ccs. We have previously shown that the endonucleolytic activity of MRE11 plays a key role in removing 5′ TOP2 adducts in G1phase. We show here that BRCA1 promotes MRE11-mediated removal of TOP2 adducts in G1phase. We disrupted theBRCA1gene in53BP1-deficient ER-positive breast cancer and B cells. The loss of BRCA1 caused marked increases of pathological TOP2ccs in G1phase following exposure to etoposide, which generates pathological TOP2ccs. We conclude that BRCA1 promotes the removal of TOP2 adducts from DSB ends for subsequent nonhomologous end joining.BRCA1-deficient cells showed a decrease in etoposide-induced MRE11 foci in G1phase, suggesting that BRCA1 repairs pathological TOP2ccs by promoting the recruitment of MRE11 to TOP2cc sites. BRCA1 depletion also leads to the increase of unrepaired DSBs upon estrogen treatment both in vitro in G1-arrested breast cancer cells and in vivo in epithelial cells of mouse mammary glands. BRCA1 thus plays a critical role in removing pathological TOP2ccs induced by estrogens as well as etoposide. We propose that BRCA1 suppresses tumorigenesis by removing estrogen-induced pathological TOP2ccs throughout the cell cycle.

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Section: Loss Of Brca1 Causes Prolonged γH2ax-focus Formation After Pmentioning

confidence: 77%

Section: Discussionmentioning

confidence: 99%

BRCA1 ensures genome integrity by eliminating estrogen-induced pathological topoisomerase II–DNA complexes

Sasanuma

Tsuda

Morimoto

et al. 2018

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

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“…Since we observed that the Brd4-CTD bound more CDK9 in the presence of Y138E and that E2 Y138E is defective for induction of E1-dependent DNA replication, we wondered whether CDK9 release from Brd4 CTD prevents origin firing. In this model, E2 would bind the CTD and release P-TEFb, allowing the CDK9 kinase to not only activate RNA polymerase but inhibit DNA polymerase, thereby preventing collision of the transcription and DNA replication complexes (34). We therefore questioned whether a CDK9 inhibitor might restore the replication function of E2 Y138E.…”

Section: Resultsmentioning

confidence: 99%

Phosphorylation of a Conserved Tyrosine in the Papillomavirus E2 Protein Regulates Brd4 Binding and Viral Replication

DeSmet

Jose

Isaq

et al. 2019

J Virol

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The papillomavirus (PV) E2 protein coordinates viral transcription and genome replication. Following a strategy to identify amino acids in E2 that are posttranslationally modified, we reported that tyrosine kinase fibroblast growth factor receptor 3 (FGFR3) complexes with and phosphorylates E2, which inhibits viral DNA replication. Here, we present several lines of evidence indicating that tyrosine (Y) 138 of HPV-31 E2 is a substrate of FGFR3. The active form of FGFR3 bound to and phosphorylated the region of amino acids (aa) 107 to 175 in HPV-31 E2. The E2 phenylalanine (F) mutant Y138F displayed reduced FGFR3-induced phosphotyrosine. A constitutive kinase-active FGFR3 inhibited wild-type (WT) E2-induced E1-dependent DNA replication, while the 138F mutant retained activity. The tyrosine to glutamic acid (E) mutant Y138E, which can mimic phosphotyrosine, failed to induce transient DNA replication, although it maintained the ability to bind and localize the viral DNA helicase E1 to the viral origin. The bromodomain-containing protein 4 (Brd4) binds to E2 and is necessary for initiation of viral DNA synthesis. Interestingly, the Y138E protein coimmunoprecipitated with full-length Brd4 but was defective for association with its C-terminal domain (CTD). These results imply that the activity of the FGFR3 kinase in the infected epithelial cell restricts the HPV replication program through phosphorylation of E2 at Y138, which interferes with E2 binding to the Brd4 CTD, and that this interaction is required for initiation of viral DNA synthesis. IMPORTANCE Human papillomaviruses (HPVs) are highly infectious pathogens that commonly infect the oropharynx and uterine cervix. The idea that posttranslational modifications of viral proteins coordinates viral genome replication is less explored. We recently discovered that fibroblast growth factor receptor 3 (FGFR3) phosphorylates the viral E2 protein. The current study demonstrates that FGFR3 phosphorylates E2 at tyrosine 138, which inhibits association with the C-terminal peptide of Brd4. This study illustrates a novel regulatory mechanism of virus-host interaction and provides insight into the role of Brd4 in viral replication.

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“…These bring us to one of the most basic questions in biology: with the same DNA template, how can cells solve the conflicts of replication and transcription? (García-Muse and Aguilera 2016; Hamperl et al 2017;Lin and Pasero 2017). It will be interesting to dissect roles played by TXR1 in replication and transcription, and how it contributes to coordinating conflicts between these two essential processes.…”

Section: Histone Methylation H3k27me1 Is Involved In the Regulation Omentioning

confidence: 99%

Our recent progress in epigenetic research using the model ciliate, Tetrahymena thermophila

Cheng

Wang

Huang

et al. 2019

Mar Life Sci Technol

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Epigenetic research focuses on heritable changes beyond the DNA sequence, which has led to a revolution in biological studies and benefits in many other fields. The well-known model ciliate, Tetrahymena thermophila offers a unique system for epigenetic studies due to its nuclear dimorphism and special mode of sexual reproduction (conjugation), as well as abundant genomic resources and genetic tools. In this paper, we summarize recent progress made by our research team and collaborators in understanding epigenetic mechanisms using Tetrahymena. This includes: (1) providing the first genome-wide base pair-resolution map of DNA N 6-methyladenine (6mA) and revealed it as an integral part of the chromatin landscape; (2) dissecting the relative contribution of cis-and trans-elements to nucleosome distribution by exploring the unique nuclear dimorphism of Tetrahymena; (3) demonstrating the epigenetic controls of RNAi-dependent Polycomb repression pathways on transposable elements, and (4) identifying a new histone monomethyltransferase, TXR1 (Tetrahymena Trithorax 1), that facilitates replication elongation through its substrate histone H3 lysine 27 monomethylation (H3K27me1).

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Transcription-Replication Conflicts: Orientation Matters

Cited by 14 publications

References 10 publications

BRCA1 ensures genome integrity by eliminating estrogen-induced pathological topoisomerase II–DNA complexes

BRCA1 ensures genome integrity by eliminating estrogen-induced pathological topoisomerase II–DNA complexes

Phosphorylation of a Conserved Tyrosine in the Papillomavirus E2 Protein Regulates Brd4 Binding and Viral Replication

Our recent progress in epigenetic research using the model ciliate, Tetrahymena thermophila

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