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Article ; Online: Transcription and genome integrity.

Ljungman, Mats

2022 Volume 118, Page(s) 103373

Abstract: Transcription can cause genome instability by promoting R-loop formation but also act as a mutation-suppressing machinery by sensing of DNA lesions leading to the activation of DNA damage signaling and transcription-coupled repair. Recovery of RNA ... ...

Abstract	Transcription can cause genome instability by promoting R-loop formation but also act as a mutation-suppressing machinery by sensing of DNA lesions leading to the activation of DNA damage signaling and transcription-coupled repair. Recovery of RNA synthesis following the resolution of repair of transcription-blocking lesions is critical to avoid apoptosis and several new factors involved in this process have recently been identified. Some DNA repair proteins are recruited to initiating RNA polymerases and this may expediate the recruitment of other factors that participate in the repair of transcription-blocking DNA lesions. Recent studies have shown that transcription of protein-coding genes does not always give rise to spliced transcripts, opening the possibility that cells may use the transcription machinery in a splicing-uncoupled manner for other purposes including surveillance of the transcribed genome.
MeSH term(s)	DNA/metabolism ; DNA Damage ; DNA Repair ; Genomic Instability ; Humans ; Transcription, Genetic
Chemical Substances	DNA (9007-49-2)
Language	English
Publishing date	2022-07-19
Publishing country	Netherlands
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	2071608-4
ISSN	1568-7856 ; 1568-7864
ISSN (online)	1568-7856
ISSN	1568-7864
DOI	10.1016/j.dnarep.2022.103373
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Article ; Online: First-in-Class NADH/Ubiquinone Oxidoreductase Core Subunit S7 (NDUFS7) Antagonist for the Treatment of Pancreatic Cancer.

Xu, Yibin / Xue, Ding / Kyani, Armita / Bankhead, Armand / Roy, Joyeeta / Ljungman, Mats / Neamati, Nouri

ACS pharmacology & translational science

2023 Volume 6, Issue 8, Page(s) 1164–1181

Abstract: Pancreatic cancer cells adapt to nutrient-scarce metabolic conditions by increasing their oxidative phosphorylation reserve to survive. Here, we present a first-in-class small-molecule NDUFS7 antagonist that inhibits oxidative phosphorylation (OXPHOS) ... ...

Abstract	Pancreatic cancer cells adapt to nutrient-scarce metabolic conditions by increasing their oxidative phosphorylation reserve to survive. Here, we present a first-in-class small-molecule NDUFS7 antagonist that inhibits oxidative phosphorylation (OXPHOS) for the treatment of pancreatic cancer. The lead compound, DX2-201, suppresses the proliferation of a panel of cell lines, and a metabolically stable analogue, DX3-213B, shows significant efficacy in a syngeneic model of pancreatic cancer. Exome sequencing of six out of six clones resistant to DX2-201 revealed a pV91M mutation in NDUFS7, providing direct evidence of its drug-binding site. In combination studies, DX2-201 showed synergy with multiple metabolic modulators, select OXPHOS inhibitors, and PARP inhibitors. Importantly, a combination with 2-deoxyglucose overcomes drug resistance in vivo. This study demonstrates that an efficacious treatment for pancreatic cancer can be achieved through inhibition of OXPHOS and direct binding to NDUFS7, providing a novel therapeutic strategy for this hard-to-treat cancer.
Language	English
Publishing date	2023-06-28
Publishing country	United States
Document type	Journal Article
ISSN	2575-9108
ISSN (online)	2575-9108
DOI	10.1021/acsptsci.3c00069
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Article ; Online: The DNA damage response--repair or despair?

Ljungman, Mats

Environmental and molecular mutagenesis

2010 Volume 51, Issue 8-9, Page(s) 879–889

Abstract: The term "the DNA damage response" (DDR) encompasses a sophisticated array of cellular initiatives set in motion as cells are exposed to DNA-damaging events. It has been known for over half a century that all organisms have the ability to restore genomic ...

Abstract	The term "the DNA damage response" (DDR) encompasses a sophisticated array of cellular initiatives set in motion as cells are exposed to DNA-damaging events. It has been known for over half a century that all organisms have the ability to restore genomic integrity through DNA repair. More recent discoveries of signal transduction pathways linking DNA damage to cell cycle arrest and apoptosis have greatly expanded our views of how cells and tissues limit mutagenesis and tumorigenesis. DNA repair not only plays a pivotal role in suppressing mutagenesis but also in the reversal of signals inducing the stress response. If repair is faulty or the cell is overwhelmed by damage, chances are that the cell will despair and be removed by apoptosis. This final fate is determined by intricate cellular dosimeters that are yet to be fully understood. Here, key findings leading to our current view of DDR are discussed as well as potential areas of importance for future studies.
MeSH term(s)	Aging ; Animals ; Apoptosis ; Cell Cycle/genetics ; DNA Damage ; DNA Repair ; Humans ; Signal Transduction
Language	English
Publishing date	2010-10
Publishing country	United States
Document type	Journal Article ; Review
ZDB-ID	639145-x
ISSN	1098-2280 ; 0893-6692
ISSN (online)	1098-2280
ISSN	0893-6692
DOI	10.1002/em.20597
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Article: KLIPP - a precision CRISPR approach to target structural variant junctions in cancer.

Yang, Huibin / Hulbatte, Radhika Suhas / Kelleher, Alan / Gratsch, Natalie / Wang, Yin / Palmbos, Philip L / Ljungman, Mats

bioRxiv : the preprint server for biology

2023

Abstract: Current cancer therapies typically give rise to dose-limiting normal tissue toxicity. We have developed KLIPP, a precision cancer approach that specifically kills cancer cells using CRISPR/Cas9 technology. The approach consists of guide RNAs that target ... ...

Abstract	Current cancer therapies typically give rise to dose-limiting normal tissue toxicity. We have developed KLIPP, a precision cancer approach that specifically kills cancer cells using CRISPR/Cas9 technology. The approach consists of guide RNAs that target cancer-specific structural variant junctions to nucleate two parts of a dCas9-conjugated endonuclease, Fok1, leading to its activation. We show that KLIPP causes induction of DNA double strand breaks (DSBs) at the targeted junctions and cell death. When cancer cells were grown orthotopically in mice, activation of Fok1 at only two junctions led to the disappearance of tumor cells in 7/11 mice. This therapeutic approach has high specificity for tumor cells and is independent of tumor-specific drivers. Individualized translation of KLIPP to patients would be transformative and lead to consistent and simplified cancer treatment decisions.
Language	English
Publishing date	2023-05-12
Publishing country	United States
Document type	Preprint
DOI	10.1101/2023.05.10.540176
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Article ; Online: Multi-omics profiling reveals key signaling pathways in ovarian cancer controlled by STAT3.

Lu, Tiangong / Bankhead, Armand / Ljungman, Mats / Neamati, Nouri

Theranostics

2019 Volume 9, Issue 19, Page(s) 5478–5496

Abstract: Inhibiting STAT3 signaling reduces tumor progression, metastasis and chemoresistance, however the precise molecular mechanism has not been fully delineated in ovarian cancer.: Methods: In this study, we generated : Results: We observed that ... ...

Abstract	Inhibiting STAT3 signaling reduces tumor progression, metastasis and chemoresistance, however the precise molecular mechanism has not been fully delineated in ovarian cancer. Methods: In this study, we generated Results: We observed that deletion of Conclusion: Our study presents a rich, multi-faceted summary of the molecular mechanisms impacted by
MeSH term(s)	Animals ; Cell Cycle ; Cell Proliferation ; Female ; Gene Expression Regulation, Neoplastic ; Humans ; Mice ; Mice, Knockout ; Ovarian Neoplasms/genetics ; Ovarian Neoplasms/metabolism ; Ovarian Neoplasms/physiopathology ; Proteomics ; Signal Transduction
Language	English
Publishing date	2019-07-28
Publishing country	Australia
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	2592097-2
ISSN	1838-7640 ; 1838-7640
ISSN (online)	1838-7640
ISSN	1838-7640
DOI	10.7150/thno.33444
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Article ; Online: Targeting the DNA damage response in cancer.

Ljungman, Mats

Chemical reviews

2009 Volume 109, Issue 7, Page(s) 2929–2950

MeSH term(s)	Antineoplastic Agents/therapeutic use ; Cell Proliferation ; Cell Survival ; DNA Damage ; DNA Repair/drug effects ; Neoplasms/drug therapy ; Neoplasms/genetics ; Neoplasms/metabolism ; Signal Transduction
Chemical Substances	Antineoplastic Agents
Language	English
Publishing date	2009-07
Publishing country	United States
Document type	Journal Article ; Review
ZDB-ID	207949-5
ISSN	1520-6890 ; 0009-2665
ISSN (online)	1520-6890
ISSN	0009-2665
DOI	10.1021/cr900047g
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Article: Characterizing nascent transcription patterns of PROMPTs, eRNAs, and readthrough transcripts in the ENCODE4 deeply profiled cell lines.

McShane, Ariel / Narayanan, Ishwarya Venkata / Paulsen, Michelle T / Ashaka, Mario / Blinkiewicz, Hailey / Yang, Nina T / Magnuson, Brian / Bedi, Karan / Wilson, Thomas E / Ljungman, Mats

bioRxiv : the preprint server for biology

2024

Abstract: Arising as co-products of canonical gene expression, transcription-associated lincRNAs, such as promoter upstream transcripts (PROMPTs), enhancer RNAs (eRNAs), and readthrough (RT) transcripts, are often regarded as byproducts of transcription, although ... ...

Abstract	Arising as co-products of canonical gene expression, transcription-associated lincRNAs, such as promoter upstream transcripts (PROMPTs), enhancer RNAs (eRNAs), and readthrough (RT) transcripts, are often regarded as byproducts of transcription, although they may be important for the expression of nearby genes. We identified regions of nascent expression of these lincRNA in 16 human cell lines using Bru-seq techniques, and found distinctly regulated patterns of PROMPT, eRNA, and RT transcription using the diverse biochemical approaches in the ENCODE4 deeply profiled cell lines collection. Transcription of these lincRNAs was influenced by sequence-specific features and the local or 3D chromatin landscape. However, these sequence and chromatin features do not describe the full spectrum of lincRNA expression variability we identify, highlighting the complexity of their regulation. This may suggest that transcription-associated lincRNAs are not merely byproducts, but rather that the transcript itself, or the act of its transcription, is important for genomic function.
Language	English
Publishing date	2024-04-09
Publishing country	United States
Document type	Preprint
DOI	10.1101/2024.04.09.588612
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Article ; Online: Dissecting regulatory pathways for transcription recovery following DNA damage reveals a non-canonical function of the histone chaperone HIRA.

Bouvier, Déborah / Ferrand, Juliette / Chevallier, Odile / Paulsen, Michelle T / Ljungman, Mats / Polo, Sophie E

Nature communications

2021 Volume 12, Issue 1, Page(s) 3835

Abstract: Transcription restart after a genotoxic challenge is a fundamental yet poorly understood process. Here, we dissect the interplay between transcription and chromatin restoration after DNA damage by focusing on the human histone chaperone complex HIRA, ... ...

Abstract	Transcription restart after a genotoxic challenge is a fundamental yet poorly understood process. Here, we dissect the interplay between transcription and chromatin restoration after DNA damage by focusing on the human histone chaperone complex HIRA, which is required for transcription recovery post UV. We demonstrate that HIRA is recruited to UV-damaged chromatin via the ubiquitin-dependent segregase VCP to deposit new H3.3 histones. However, this local activity of HIRA is dispensable for transcription recovery. Instead, we reveal a genome-wide function of HIRA in transcription restart that is independent of new H3.3 and not restricted to UV-damaged loci. HIRA coordinates with ASF1B to control transcription restart by two independent pathways: by stabilising the associated subunit UBN2 and by reducing the expression of the transcription repressor ATF3. Thus, HIRA primes UV-damaged chromatin for transcription restart at least in part by relieving transcription inhibition rather than by depositing new H3.3 as an activating bookmark.
MeSH term(s)	Activating Transcription Factor 3/genetics ; Activating Transcription Factor 3/metabolism ; Cell Cycle Proteins/genetics ; Cell Cycle Proteins/metabolism ; Cell Line, Tumor ; Cells, Cultured ; Chromatin/genetics ; Chromatin/metabolism ; Chromatin/radiation effects ; DNA Damage ; DNA Repair ; HeLa Cells ; Histone Chaperones/genetics ; Histone Chaperones/metabolism ; Histones/metabolism ; Humans ; Signal Transduction/genetics ; Transcription Factors/genetics ; Transcription Factors/metabolism ; Transcription, Genetic ; Ultraviolet Rays ; Valosin Containing Protein/genetics ; Valosin Containing Protein/metabolism
Chemical Substances	ASF1B protein, human ; ATF3 protein, human ; Activating Transcription Factor 3 ; Cell Cycle Proteins ; Chromatin ; HIRA protein, human ; Histone Chaperones ; Histones ; Transcription Factors ; Valosin Containing Protein (EC 3.6.4.6)
Language	English
Publishing date	2021-06-22
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2553671-0
ISSN	2041-1723 ; 2041-1723
ISSN (online)	2041-1723
ISSN	2041-1723
DOI	10.1038/s41467-021-24153-1
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Article ; Online: Co-transcriptional splicing efficiencies differ within genes and between cell types.

Bedi, Karan / Magnuson, Brian R / Narayanan, Ishwarya / Paulsen, Michelle / Wilson, Thomas E / Ljungman, Mats

RNA (New York, N.Y.)

2021

Abstract: Pre-mRNA splicing is carried out by the spliceosome and involves splice site recognition, removal of introns, and ligation of exons. Components of the spliceosome have been shown to interact with the elongating RNA polymerase II (RNAPII) which is thought ...

Abstract	Pre-mRNA splicing is carried out by the spliceosome and involves splice site recognition, removal of introns, and ligation of exons. Components of the spliceosome have been shown to interact with the elongating RNA polymerase II (RNAPII) which is thought to allow splicing to occur concurrently with transcription. However, little is known about the regulation and efficiency of co-transcriptional splicing in human cells. In this study, we used Bru-seq and BruChase-seq to determine the co-transcriptional splicing efficiencies of 17,000 introns expressed across 6 human cell lines. We found that less than half of all introns across these 6 cell lines were co-transcriptionally spliced. Splicing efficiencies for individual introns showed variations across cell lines, suggesting that splicing may be regulated in a cell-type specific manner. Moreover, the splicing efficiency of introns varied within genes. The efficiency of co-transcriptional splicing did not correlate with gene length, intron position, splice site strengths, or the intron/neighboring exons GC content. However, we identified binding signals from multiple RNA binding proteins (RBPs) that correlated with splicing efficiency, including core spliceosomal machinery components-such as SF3B4, U2AF1 and U2AF2 showing higher binding signals in poorly spliced introns. In addition, multiple RBPs, such as BUD13, PUM1 and SND1, showed preferential binding in exons that flank introns with high splicing efficiencies. The nascent RNA splicing patterns presented here across multiple cell types add to our understanding of the complexity in RNA splicing, wherein RNA-binding proteins may play important roles in determining splicing outcomes in a cell type- and intron-specific manner.
Language	English
Publishing date	2021-05-11
Publishing country	United States
Document type	Journal Article
ZDB-ID	1241540-6
ISSN	1469-9001 ; 1355-8382
ISSN (online)	1469-9001
ISSN	1355-8382
DOI	10.1261/rna.078662.120
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Article ; Online: The transcription stress response.

Ljungman, Mats

Cell cycle (Georgetown, Tex.)

2007 Volume 6, Issue 18, Page(s) 2252–2257

Abstract: The RNA polymerase II transcription machinery acts as a molecular motor that traverses large parts of the genome on a regular basis. It has been suggested that the transcription machinery may play an important role in sensing DNA damage and activating ... ...

Abstract	The RNA polymerase II transcription machinery acts as a molecular motor that traverses large parts of the genome on a regular basis. It has been suggested that the transcription machinery may play an important role in sensing DNA damage and activating DNA repair and stress response pathways when stalled at blocking lesions. We have collectively termed the activation of these different pathways as the transcription stress response. Recently, it was shown that the ATR kinase and the single-strand DNA-binding protein RPA mediate the phosphorylation of p53 following blockage of transcription elongation. This ATR-mediated phosphorylation occurs even when transcription elongation is blocked in the absence of DNA damage, suggesting that ATR and RPA senses the consequences of blocked transcription elongation rather than sensing DNA lesions directly. It is proposed that the transcription stress response activated by blockage of transcription may play an important role in safeguarding the genome from DNA damage and thus act to suppress tumorigenesis.
MeSH term(s)	Animals ; DNA Damage/physiology ; Humans ; Oxidative Stress/genetics ; RNA Polymerase II/genetics ; RNA Polymerase II/metabolism ; Transcription, Genetic/physiology
Chemical Substances	RNA Polymerase II (EC 2.7.7.-)
Language	English
Publishing date	2007-07-16
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	2146183-1
ISSN	1551-4005 ; 1538-4101 ; 1554-8627
ISSN (online)	1551-4005
ISSN	1538-4101 ; 1554-8627
DOI	10.4161/cc.6.18.4751
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