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Article ; Online: Walking a tightrope: The complex balancing act of R-loops in genome stability.

Brickner, Joshua R / Garzon, Jada L / Cimprich, Karlene A

2022 Volume 82, Issue 12, Page(s) 2267–2297

Abstract: Although transcription is an essential cellular process, it is paradoxically also a well-recognized cause of genomic instability. R-loops, non-B DNA structures formed when nascent RNA hybridizes to DNA to displace the non-template strand as single- ... ...

Abstract	Although transcription is an essential cellular process, it is paradoxically also a well-recognized cause of genomic instability. R-loops, non-B DNA structures formed when nascent RNA hybridizes to DNA to displace the non-template strand as single-stranded DNA (ssDNA), are partially responsible for this instability. Yet, recent work has begun to elucidate regulatory roles for R-loops in maintaining the genome. In this review, we discuss the cellular contexts in which R-loops contribute to genomic instability, particularly during DNA replication and double-strand break (DSB) repair. We also summarize the evidence that R-loops participate as an intermediate during repair and may influence pathway choice to preserve genomic integrity. Finally, we discuss the immunogenic potential of R-loops and highlight their links to disease should they become pathogenic.
MeSH term(s)	DNA/metabolism ; DNA Repair ; DNA Replication ; DNA, Single-Stranded/genetics ; Genomic Instability ; Humans ; R-Loop Structures/genetics ; Transcription, Genetic
Chemical Substances	DNA, Single-Stranded ; DNA (9007-49-2)
Language	English
Publishing date	2022-05-03
Publishing country	United States
Document type	Journal Article ; Review ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural
ZDB-ID	1415236-8
ISSN	1097-4164 ; 1097-2765
ISSN (online)	1097-4164
ISSN	1097-2765
DOI	10.1016/j.molcel.2022.04.014
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article: Walking a tightrope: The complex balancing act of R-loops in genome stability

Brickner, Joshua R. / Garzon, Jada L. / Cimprich, Karlene A.

Molecular cell. 2022 June 16, v. 82, no. 12

2022

Abstract	Although transcription is an essential cellular process, it is paradoxically also a well-recognized cause of genomic instability. R-loops, non-B DNA structures formed when nascent RNA hybridizes to DNA to displace the non-template strand as single-stranded DNA (ssDNA), are partially responsible for this instability. Yet, recent work has begun to elucidate regulatory roles for R-loops in maintaining the genome. In this review, we discuss the cellular contexts in which R-loops contribute to genomic instability, particularly during DNA replication and double-strand break (DSB) repair. We also summarize the evidence that R-loops participate as an intermediate during repair and may influence pathway choice to preserve genomic integrity. Finally, we discuss the immunogenic potential of R-loops and highlight their links to disease should they become pathogenic.
Keywords	DNA replication ; RNA ; genetic instability ; genome ; genomics ; single-stranded DNA
Language	English
Dates of publication	2022-0616
Size	p. 2267-2297.
Publishing place	Elsevier Inc.
Document type	Article
ZDB-ID	1415236-8
ISSN	1097-4164 ; 1097-2765
ISSN (online)	1097-4164
ISSN	1097-2765
DOI	10.1016/j.molcel.2022.04.014
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Article ; Online: Cyclin-Dependent Kinase-Mediated Phosphorylation of FANCD2 Promotes Mitotic Fidelity.

Cantres-Velez, Juan A / Blaize, Justin L / Vierra, David A / Boisvert, Rebecca A / Garzon, Jada L / Piraino, Benjamin / Tan, Winnie / Deans, Andrew J / Howlett, Niall G

Molecular and cellular biology

2021 Volume 41, Issue 8, Page(s) e0023421

Abstract: Fanconi anemia (FA) is a rare genetic disease characterized by increased risk for bone marrow failure and cancer. The FA proteins function together to repair damaged DNA. A central step in the activation of the FA pathway is the monoubiquitination of the ...

Abstract	Fanconi anemia (FA) is a rare genetic disease characterized by increased risk for bone marrow failure and cancer. The FA proteins function together to repair damaged DNA. A central step in the activation of the FA pathway is the monoubiquitination of the FANCD2 and FANCI proteins, which occurs upon exposure to DNA-damaging agents and during the S phase of the cell cycle. The regulatory mechanisms governing S-phase monoubiquitination, in particular, are poorly understood. In this study, we have identified a cyclin-dependent kinase (CDK) regulatory phosphosite (S592) proximal to the site of FANCD2 monoubiquitination. FANCD2 S592 phosphorylation was detected by liquid chromatography-tandem mass spectrometry (LC-MS/MS) and by immunoblotting with an S592 phospho-specific antibody. Mutation of S592 leads to abrogated monoubiquitination of FANCD2 during the S phase. Furthermore, FA-D2 (
MeSH term(s)	Cell Cycle/physiology ; Cyclin-Dependent Kinases/genetics ; Cyclin-Dependent Kinases/metabolism ; Fanconi Anemia/genetics ; Fanconi Anemia/metabolism ; Fanconi Anemia Complementation Group D2 Protein/genetics ; Fanconi Anemia Complementation Group D2 Protein/metabolism ; Fanconi Anemia Complementation Group Proteins/chemistry ; Fanconi Anemia Complementation Group Proteins/genetics ; Fanconi Anemia Complementation Group Proteins/metabolism ; Humans ; Phosphorylation/physiology ; Tandem Mass Spectrometry/methods ; Ubiquitination/physiology
Chemical Substances	Fanconi Anemia Complementation Group D2 Protein ; Fanconi Anemia Complementation Group Proteins ; Cyclin-Dependent Kinases (EC 2.7.11.22)
Language	English
Publishing date	2021-07-23
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	779397-2
ISSN	1098-5549 ; 0270-7306
ISSN (online)	1098-5549
ISSN	0270-7306
DOI	10.1128/MCB.00234-21
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Article ; Online: Cyclin-Dependent Kinase-Mediated Phosphorylation of FANCD2 Promotes Mitotic Fidelity

Cantres-Velez, Juan A. / Blaize, Justin L. / Vierra, David A. / Boisvert, Rebecca A. / Garzon, Jada L. / Piraino, Benjamin / Tan, Winnie / Deans, Andrew J. / Howlett, Niall G.

Molecular and Cellular Biology. 2021 Aug. 1, v. 41, no. 8 p.e00234-21-

2021

Abstract	Fanconi anemia (FA) is a rare genetic disease characterized by increased risk for bone marrow failure and cancer. The FA proteins function together to repair damaged DNA. A central step in the activation of the FA pathway is the monoubiquitination of the FANCD2 and FANCI proteins, which occurs upon exposure to DNA-damaging agents and during the S phase of the cell cycle. The regulatory mechanisms governing S-phase monoubiquitination, in particular, are poorly understood. In this study, we have identified a cyclin-dependent kinase (CDK) regulatory phosphosite (S592) proximal to the site of FANCD2 monoubiquitination. FANCD2 S592 phosphorylation was detected by liquid chromatography-tandem mass spectrometry (LC-MS/MS) and by immunoblotting with an S592 phospho-specific antibody. Mutation of S592 leads to abrogated monoubiquitination of FANCD2 during the S phase. Furthermore, FA-D2 (FANCD2⁻/⁻) patient cells expressing S592 mutants display reduced proliferation under conditions of replication stress and increased mitotic aberrations, including micronuclei and multinucleated cells. Our findings describe a novel cell cycle-specific regulatory mechanism for the FANCD2 protein that promotes mitotic fidelity.
Keywords	DNA ; Fanconi anemia ; antibodies ; bone marrow ; cyclin-dependent kinase ; immunoblotting ; interphase ; liquid chromatography ; mitosis ; mutation ; patients ; phosphorylation ; risk ; tandem mass spectrometry ; FANCD2 ; CDK phosphorylation ; cell cycle ; chromosome stability ; ubiquitination ; ubiquitin
Language	English
Dates of publication	2021-0801
Publishing place	Taylor & Francis
Document type	Article ; Online
ZDB-ID	779397-2
ISSN	1098-5549 ; 0270-7306
ISSN (online)	1098-5549
ISSN	0270-7306
DOI	10.1128/MCB.00234-21
Database	NAL-Catalogue (AGRICOLA)

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Article ; Online: Modulation of the Fanconi anemia pathway

Vierra, David A / Garzon, Jada L / Rego, Meghan A / Adroved, Morganne M / Mauro, Maurizio / Howlett, Niall G

Oncotarget

2017 Volume 8, Issue 44, Page(s) 76443–76457

Abstract: Fanconi anemia (FA) is a rare disease characterized by congenital defects, bone marrow failure, and atypically early-onset cancers. The FA proteins function cooperatively to repair DNA interstrand crosslinks. A major step in the activation of the pathway ...

Abstract	Fanconi anemia (FA) is a rare disease characterized by congenital defects, bone marrow failure, and atypically early-onset cancers. The FA proteins function cooperatively to repair DNA interstrand crosslinks. A major step in the activation of the pathway is the monoubiquitination of the FANCD2 and FANCI proteins, and their recruitment to chromatin-associated nuclear foci. The regulation and function of FANCD2 and FANCI, however, is poorly understood. In addition, how chromatin state impacts pathway activation is also unknown. In this study, we have examined the influence of chromatin state on the activation of the FA pathway. We describe potent activation of FANCD2 and FANCI monoubiquitination and nuclear foci formation following treatment of cells with the histone methyltransferase inhibitor BRD4770. BRD4770-induced activation of the pathway does not occur
Language	English
Publishing date	2017-09-29
Publishing country	United States
Document type	Journal Article
ZDB-ID	2560162-3
ISSN	1949-2553 ; 1949-2553
ISSN (online)	1949-2553
ISSN	1949-2553
DOI	10.18632/oncotarget.19470
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Article ; Online: Phase 1b trial of tagraxofusp in combination with azacitidine with or without venetoclax in acute myeloid leukemia.

Lane, Andrew A / Garcia, Jacqueline S / Raulston, Evangeline G / Garzon, Jada L / Galinsky, Ilene / Baxter, Emilie W / Leonard, Rebecca / DeAngelo, Daniel J / Luskin, Marlise R / Reilly, Christopher R / Stahl, Maximilian / Stone, Richard M / Vedula, Rahul S / Wadleigh, Martha M / Winer, Eric S / Mughal, Tariq / Brooks, Christopher / Gupta, Ira V / Stevenson, Kristen E /

Neuberg, Donna S / Ren, Siyang / Keating, Julia / Konopleva, Marina / Stein, Anthony / Pemmaraju, Naveen

Blood advances

2023 Volume 8, Issue 3, Page(s) 591–602

Abstract: Abstract: CD123, a subunit of the interleukin-3 receptor, is expressed on ∼80% of acute myeloid leukemias (AMLs). Tagraxofusp (TAG), recombinant interleukin-3 fused to a truncated diphtheria toxin payload, is a first-in-class drug targeting CD123 ... ...

Abstract	Abstract: CD123, a subunit of the interleukin-3 receptor, is expressed on ∼80% of acute myeloid leukemias (AMLs). Tagraxofusp (TAG), recombinant interleukin-3 fused to a truncated diphtheria toxin payload, is a first-in-class drug targeting CD123 approved for treatment of blastic plasmacytoid dendritic cell neoplasm. We previously found that AMLs with acquired resistance to TAG were re-sensitized by the DNA hypomethylating agent azacitidine (AZA) and that TAG-exposed cells became more dependent on the antiapoptotic molecule BCL-2. Here, we report a phase 1b study in 56 adults with CD123-positive AML or high-risk myelodysplastic syndrome (MDS), first combining TAG with AZA in AML/MDS, and subsequently TAG, AZA, and the BCL-2 inhibitor venetoclax (VEN) in AML. Adverse events with 3-day TAG dosing were as expected, without indication of increased toxicity of TAG or AZA+/-VEN in combination. The recommended phase 2 dose of TAG was 12 μg/kg/day for 3 days, with 7-day AZA +/- 21-day VEN. In an expansion cohort of 26 patients (median age 71) with previously untreated European LeukemiaNet adverse-risk AML (50% TP53 mutated), triplet TAG-AZA-VEN induced response in 69% (n=18/26; 39% complete remission [CR], 19% complete remission with incomplete count recovery [CRi], 12% morphologic leukemia-free state [MLFS]). Among 13 patients with TP53 mutations, 7/13 (54%) achieved CR/CRi/MLFS (CR = 4, CRi = 2, MLFS = 1). Twelve of 17 (71%) tested responders had no flow measurable residual disease. Median overall survival and progression-free survival were 14 months (95% CI, 9.5-NA) and 8.5 months (95% CI, 5.1-NA), respectively. In summary, TAG-AZA-VEN shows encouraging safety and activity in high-risk AML, including TP53-mutated disease, supporting further clinical development of TAG combinations. The study was registered on ClinicalTrials.gov as #NCT03113643.
MeSH term(s)	Adult ; Aged ; Humans ; Azacitidine/therapeutic use ; Bridged Bicyclo Compounds, Heterocyclic ; Interleukin-3 Receptor alpha Subunit ; Leukemia, Myeloid, Acute/genetics ; Myelodysplastic Syndromes/genetics ; Proto-Oncogene Proteins c-bcl-2 ; Recombinant Fusion Proteins ; Sulfonamides
Chemical Substances	Azacitidine (M801H13NRU) ; Bridged Bicyclo Compounds, Heterocyclic ; Interleukin-3 Receptor alpha Subunit ; Proto-Oncogene Proteins c-bcl-2 ; Recombinant Fusion Proteins ; Sulfonamides ; tagraxofusp (8ZHS5657EH) ; venetoclax (N54AIC43PW)
Language	English
Publishing date	2023-12-05
Publishing country	United States
Document type	Clinical Trial, Phase I ; Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural
ZDB-ID	2915908-8
ISSN	2473-9537 ; 2473-9529
ISSN (online)	2473-9537
ISSN	2473-9529
DOI	10.1182/bloodadvances.2023011721
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Article ; Online: FANCD2 Binding to H4K20me2 via a Methyl-Binding Domain Is Essential for Efficient DNA Cross-Link Repair.

Paquin, Karissa L / Mamrak, Nicholas E / Garzon, Jada L / Cantres-Velez, Juan A / Azzinaro, Paul A / Vuono, Elizabeth A / Lima, Kevin E / Camberg, Jodi L / Howlett, Niall G

Molecular and cellular biology

2019 Volume 39, Issue 15

Abstract: Fanconi anemia (FA) is an inherited disease characterized by bone marrow failure and increased cancer risk. FA is caused by mutation of any 1 of 22 genes, and the FA proteins function cooperatively to repair DNA interstrand cross-links (ICLs). A central ... ...

Abstract	Fanconi anemia (FA) is an inherited disease characterized by bone marrow failure and increased cancer risk. FA is caused by mutation of any 1 of 22 genes, and the FA proteins function cooperatively to repair DNA interstrand cross-links (ICLs). A central step in the activation of the FA pathway is the monoubiquitination of the FANCD2 and FANCI proteins, which occurs within chromatin. How FANCD2 and FANCI are anchored to chromatin remains unknown. In this study, we identify and characterize a FANCD2 histone-binding domain (HBD) and embedded methyl-lysine-binding domain (MBD) and demonstrate binding specificity for H4K20me2. Disruption of the HBD/MBD compromises FANCD2 chromatin binding and nuclear focus formation and its ability to promote error-free DNA interstrand cross-link repair, leading to increased error-prone repair and genome instability. Our study functionally describes the first FA protein chromatin reader domain and establishes an important link between this human genetic disease and chromatin plasticity.
MeSH term(s)	Binding Sites ; Cell Line ; Chromatin/metabolism ; DNA Repair ; Fanconi Anemia/genetics ; Fanconi Anemia Complementation Group D2 Protein/chemistry ; Fanconi Anemia Complementation Group D2 Protein/genetics ; Fanconi Anemia Complementation Group D2 Protein/metabolism ; Genomic Instability ; HeLa Cells ; Histones/chemistry ; Histones/metabolism ; Humans ; Models, Molecular ; Protein Binding ; Protein Conformation
Chemical Substances	Chromatin ; FANCD2 protein, human ; Fanconi Anemia Complementation Group D2 Protein ; Histones
Language	English
Publishing date	2019-07-16
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	779397-2
ISSN	1098-5549 ; 0270-7306
ISSN (online)	1098-5549
ISSN	0270-7306
DOI	10.1128/MCB.00194-19
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: FANCD2 Binding to H4K20me2 via a Methyl-Binding Domain Is Essential for Efficient DNA Cross-Link Repair

Paquin, Karissa L. / Mamrak, Nicholas E. / Garzon, Jada L. / Cantres-Velez, Juan A. / Azzinaro, Paul A. / Vuono, Elizabeth A. / Lima, Kevin E. / Camberg, Jodi L. / Howlett, Niall G.

Molecular and Cellular Biology. 2019 Aug. 1, v. 39, no. 15 p.e00194-19-

2019

Abstract	Fanconi anemia (FA) is an inherited disease characterized by bone marrow failure and increased cancer risk. FA is caused by mutation of any 1 of 22 genes, and the FA proteins function cooperatively to repair DNA interstrand cross-links (ICLs). A central step in the activation of the FA pathway is the monoubiquitination of the FANCD2 and FANCI proteins, which occurs within chromatin. How FANCD2 and FANCI are anchored to chromatin remains unknown. In this study, we identify and characterize a FANCD2 histone-binding domain (HBD) and embedded methyl-lysine-binding domain (MBD) and demonstrate binding specificity for H4K20me2. Disruption of the HBD/MBD compromises FANCD2 chromatin binding and nuclear focus formation and its ability to promote error-free DNA interstrand cross-link repair, leading to increased error-prone repair and genome instability. Our study functionally describes the first FA protein chromatin reader domain and establishes an important link between this human genetic disease and chromatin plasticity.
Keywords	DNA ; DNA repair ; Fanconi anemia ; bone marrow ; chromatin ; crosslinking ; genetic instability ; humans ; plasticity ; risk ; genome instability ; ubiquitin
Language	English
Dates of publication	2019-0801
Publishing place	Taylor & Francis
Document type	Article ; Online
ZDB-ID	779397-2
ISSN	1098-5549 ; 0270-7306
ISSN (online)	1098-5549
ISSN	0270-7306
DOI	10.1128/MCB.00194-19
Database	NAL-Catalogue (AGRICOLA)

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