PCNA Unloading Is Negatively Regulated by BET Proteins

Kang, Mi-Sun; Kim, Jin-Woo; Ryu, Eunjin; Ha, Na Young; Hwang, Sunyoung; Kim, Byung-Gyu; Sun, Jae; Kim, Yeong Jae; Hwang, Jung Me; Myung, Kyungjae; Kang, Sung-Myung

doi:10.1016/j.celrep.2019.11.114

Cited by 28 publications

(23 citation statements)

References 38 publications

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“…Indeed, BET inhibition has resulted in DNA replication stress (Bowry et al, 2018) and replication re-initiation (Zhang et al, 2018). BET proteins are also implicated in the regulation of proliferating cell nuclear antigen unloading (Kang et al, 2019). The SWAN analysis presented here underscores the importance of BET proteins in the biology of DNA replication and serves as an example of SWAN usage outside of cancer genetics.…”

Section: Resultsmentioning

confidence: 99%

SWAN Identification of Common Aneuploidy-Based Oncogenic Drivers

Jones

et al. 2021

Preprint

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Haploinsufficiency drives Darwinian evolution. Siblings, while alike in many aspects, differ due to monoallelic differences inherited from each parent. In cancer, solid tumors exhibit aneuploid genetics resulting in hundreds to thousands of monoallelic gene-level copy-number alterations (CNAs) in each tumor. Aneuploidy patterns are heterogeneous, posing a challenge to identify drivers in this high-noise genetic environment. Here, we developed Shifted Weighted Annotation Network (SWAN) analysis to assess biology impacted by cumulative monoallelic changes. SWAN enables an integrated pathway-network analysis of CNAs, RNA expression, and mutations via a simple web platform. SWAN is optimized to best prioritize known and novel tumor suppressors and oncogenes, thereby identifying drivers and potential druggable vulnerabilities within cancer CNAs. Protein homeostasis, phospholipid dephosphorylation, and ion transport pathways are commonly suppressed. An atlas of CNA pathways altered in each cancer type is released. These CNA network shifts highlight new, attractive targets to exploit in solid tumors.

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Section: Resultsmentioning

confidence: 99%

SWAN Identification of Common Aneuploidy-Based Oncogenic Drivers

Jones

et al. 2021

Preprint

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“…Transcription of the reverse strand may be toxic because of collision with DNA replication, which may occur predominantly in one direction as the repeats themselves have inefficient origins of replication (12) . Intriguingly, BRD4 interacts with PCNA, which is highly enriched on the lagging strand (73) . This could account for strand specificity of BRD4-dependent transcripts, which DICER1 would normally remove from the lagging strand to avoid collisions during replication.…”

Section: Discussionmentioning

confidence: 99%

Dicer promotes genome stability via the bromodomain transcriptional co-activator Brd4

Gutbrod

Roche

Steinberg

et al. 2021

Preprint

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RNA interference is essential for transcriptional silencing and genome stability, but conservation of this role in mammals has been difficult to demonstrate. Dicer1-/- mouse embryonic stem cells have microRNA-independent proliferation defects, and we conducted a CRISPR-Cas9 screen to restore viability. We identified suppressor mutations in transcriptional activators, H3K9 methyltransferases, and chromosome segregation factors, strongly resembling Dicer suppressors in fission yeast. Suppressors rescued chromosomal defects, and reversed strand-specific transcription of major satellite repeats in Dicer1-/-. The strongest suppressors were in Brd4, and in the transcriptional elongator/histone acetyltransferase Elp3. Using viable mutants and pharmaceutical inhibitors, we demonstrate that deletion of specific residues in Brd4 rescue genome instability defects of Dicer1-/- in both mammalian cells and fission yeast, implicating Dicer in coordinating transcription and replication of satellite repeats.SummaryReplication and segregation defects in Dicer1-/- stem cells depend on centromeric transcription by Brd4, and are deeply conserved in fission yeast.

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“…All the 32 homozygous mutants grew normally until 48 hpf with only four mutants showing morphological malformation and hematopoietic defects before 6 dpf, in line with observations that genomic homeostasis is linked to hematopoiesis (Botthof et al, 2017, Marsh et al, 2018, Farres et al, 2015). Mutants of pcna and atad5a , two critical genes for DNA replication (Kang et al, 2019a), showed reduced proliferation and induced apoptosis in the blood precursors at the CHT, while ddb1 homozygous mutants showed loss of HSPCs caused by reduced proliferation. PCNA and ATAD5 are critical for not only general DNA replication but also for the maintenance of replication fork stability (Park et al, 2019).…”

Section: Discussionmentioning

confidence: 99%

High-throughput generation and phenotypic characterization of zebrafish CRISPR mutants of DNA repair genes

Shin

Nakhro

et al. 2020

Preprint

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A systematic knowledge of the roles of DNA repair genes at the level of the organism has been limited largely due to the lack of appropriate animal models and experimental techniques. Zebrafish has become a powerful vertebrate genetic model system with availability due to the ease of genome editing and large-scale phenotype screening. Here, we generated zebrafish loss-of-function mutants for 33 DNA repair and replication genes through multiplexed CRISPR/Cas9-mediated mutagenesis. High-throughput phenotypic characterization of our mutant collection revealed that four genes (atad5a, ddb1, pcid2, pcna) are essential for proper embryonic development and hematopoiesis; seven genes (apex1, atrip, ino80, mre11a, shfm1, telo2, wrn) are required for growth and development during juvenile stage and six genes (blm, brca2, fanci, rad51, rad54l, rtel1) play critical roles in sex development. Furthermore, mutation in seven genes (atad5a, brca2, pcid2, polk, rad51, shfm1, xrcc1) displayed hypersensitivity to DNA damage agents. Further characterization of atad5a-/- mutants demonstrated that Atad5a is required for normal brain development and that its loss induces ATM-p53 dependent apoptosis in the brain. Our zebrafish mutant collection provides a unique resource for understanding of the roles of DNA repair genes at the organismal level.

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PCNA Unloading Is Negatively Regulated by BET Proteins

Abstract: Highlights d ATAD5 and BRD4 are enriched on nascent DNA d A conserved region upstream of ATAD5 PCNA-unloading domain binds to BRD4 ET domain d Acetyl-histone-bound BRD4 inhibits PCNA unloading by ATAD5-RLC on nascent DNA

Cited by 28 publications

References 38 publications

SWAN Identification of Common Aneuploidy-Based Oncogenic Drivers

SWAN Identification of Common Aneuploidy-Based Oncogenic Drivers

Dicer promotes genome stability via the bromodomain transcriptional co-activator Brd4

High-throughput generation and phenotypic characterization of zebrafish CRISPR mutants of DNA repair genes

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