The function and regulation of ADP-ribosylation in the DNA damage response DOI Creative Commons
Lena Duma, Ivan Ahel

Biochemical Society Transactions, Год журнала: 2023, Номер 51(3), С. 995 - 1008

Опубликована: Май 12, 2023

ADP-ribosylation is a post-translational modification involved in DNA damage response (DDR). In higher organisms it synthesised by PARP 1–3, strand break sensors. Recent advances have identified serine residues as the most common targets for during DDR. To ADP-ribosylate serine, PARPs require an accessory factor, HPF1 which completes catalytic domain. Through ADP-ribosylation, recruit variety of factors to site and control their activities. However, timely removal also key genome stability mostly performed two hydrolases: PARG ARH3. Here, we describe writers, readers erasers contribution mounting We discuss use inhibitors cancer therapy ways tackle PARPi treatment resistance.

Язык: Английский

Transcriptional Response to Hypoxia: The Role of HIF-1-Associated Co-Regulators DOI Creative Commons

Angelos Yfantis,

Ilias Mylonis, Georgia Chachami

и другие.

Cells, Год журнала: 2023, Номер 12(5), С. 798 - 798

Опубликована: Март 3, 2023

The Hypoxia Inducible Factor 1 (HIF-1) plays a major role in the cellular response to hypoxia by regulating expression of many genes involved adaptive processes that allow cell survival under low oxygen conditions. Adaptation hypoxic tumor micro-environment is also critical for cancer proliferation and therefore HIF-1 considered valid therapeutical target. Despite huge progress understanding regulation activity levels or oncogenic pathways, way interacts with chromatin transcriptional machinery order activate its target still matter intense investigation. Recent studies have identified several different HIF-1- chromatin-associated co-regulators play important roles general HIF-1, independent levels, as well selection binding sites, promoters genes, which, however, often depends on context. We review here these examine their effect compilation well-characterized direct assess range involvement hypoxia. Delineating mode significance interaction between associated may offer new attractive specific targets anticancer therapy.

Язык: Английский

Процитировано

54
NAD+ Homeostasis and NAD+-Consuming Enzymes: Implications for Vascular Health DOI Creative Commons
Roberto Campagna, Arianna Vignini

Antioxidants, Год журнала: 2023, Номер 12(2), С. 376 - 376

Опубликована: Фев. 4, 2023

Nicotinamide adenine dinucleotide (NAD+) is a ubiquitous metabolite that takes part in many key redox reactions. NAD+ biosynthesis and NAD+-consuming enzymes have been attracting markedly increasing interest since they demonstrated to be involved several crucial biological pathways, impacting genes transcription, cellular signaling, cell cycle regulation. As consequence, pathological conditions are associated with an impairment of intracellular levels, directly or indirectly, which include cardiovascular diseases, obesity, neurodegenerative cancer, aging. In this review, we describe the general pathways starting from different precursors, analyzing actual state-of-art administration precursors blocking NAD+-dependent as strategies increase levels counteract decline ageing. Subsequently, focus on disease-related age-related alterations homeostasis endothelium consequent vascular dysfunction, significantly contributes wide group disorders.

Язык: Английский

Процитировано

42
The functions and mechanisms of post-translational modification in protein regulators of RNA methylation: Current status and future perspectives DOI
Youming Chen,

Zuli Jiang,

Ying Yang

и другие.

International Journal of Biological Macromolecules, Год журнала: 2023, Номер 253, С. 126773 - 126773

Опубликована: Сен. 9, 2023

Язык: Английский

Процитировано

23
PARP1 at the crossroad of cellular senescence and nucleolar processes DOI

Kinga Kołacz,

Agnieszka Robaszkiewicz

Ageing Research Reviews, Год журнала: 2024, Номер 94, С. 102206 - 102206

Опубликована: Янв. 24, 2024

Язык: Английский

Процитировано

8
Targeting latent viral infection in EBV-associated lymphomas DOI Creative Commons
Isabella Y. Kong, Lisa Giulino‐Roth

Frontiers in Immunology, Год журнала: 2024, Номер 15

Опубликована: Фев. 23, 2024

Epstein-Barr virus (EBV) contributes to the development of a significant subset human lymphomas. As herpes virus, EBV can transition between lytic state which is required establish infection and latent where limited number viral antigens are expressed allows infected cells escape immune surveillance. Three broad latency programs have been described defined by expression proteins RNA, with I being most restrictive expressing only nuclear antigen 1 (EBNA1) EBV-encoded small RNAs (EBERs) III full panel genes including membrane 2 (LMP1/2), EBNA 2, 3, leader protein (LP) induce robust T-cell response. The therapeutic use EBV-specific T-cells has advanced treatment EBV-associated lymphoma, however this approach effective against lymphomas that express II or program. Latency tumors such as Burkitt lymphoma (BL) diffuse large B-cell (DLBCL) evade host response resistant therapies. Thus, strategies for inducing switch from program in EBV+ investigated mechanisms sensitize mediated killing. Here, we review what known about establishment regulation B-cells, role convert II/III.

Язык: Английский

Процитировано

8
Multifaceted Role of PARP1 in Maintaining Genome Stability Through Its Binding to Alternative DNA Structures DOI Creative Commons

Natalie Laspata,

Daniela Muoio, Elise Fouquerel

и другие.

Journal of Molecular Biology, Год журнала: 2023, Номер 436(1), С. 168207 - 168207

Опубликована: Июль 20, 2023

Alternative DNA structures that differ from the canonical B-form of can arise repetitive sequences and play beneficial roles in many cellular processes such as gene regulation chromatin organization. However, they also threaten genomic stability several ways including mutagenesis collisions with replication and/or transcription machinery, which lead to instability is associated human disease. Thus, careful non-B-DNA structure formation resolution crucial for maintenance genome integrity. Several protein factors have been demonstrated associate alternative facilitate their removal, one ADP-ribose transferase (ART) PARP1 (also called ADP-ribosyltransferase diphtheria toxin-like 1 or ARTD1), a multifaceted repair enzyme recognizes single- double-stranded breaks synthesizes chains poly (ADP-ribose) (PAR) recruit proteins. It now well appreciated nucleic acid beyond lesions, stalled forks, hairpins cruciforms, R-loops, G-quadruplexes (G4 DNA). In this review, we summarize current evidence direct association each these aforementioned structures, discuss role prevention structure-induced genetic instability. We will focus on mechanisms recognition binding by structure-based stimulation catalytic activity upon binding. Finally, some outstanding gaps literature offer speculative insight questions remain be experimentally addressed.

Язык: Английский

Процитировано

20
MTHFD2 in healthy and cancer cells: Canonical and non-canonical functions DOI Creative Commons
Natalia Pardo‐Lorente, Sara Sdelci

npj Metabolic Health and Disease, Год журнала: 2024, Номер 2(1)

Опубликована: Март 15, 2024

Abstract Methylenetetrahydrofolate dehydrogenase 2 (MTHFD2) is a mitochondrial enzyme of the folate-mediated one-carbon metabolism pathway. MTHFD2 has become highly attractive therapeutic target due to its consistent upregulation in cancer tissues and major contribution tumor progression, although it also performs vital functions proliferating healthy cells. Here, we review diversity canonical non-canonical this key metabolic under physiological conditions carcinogenesis. We provide an overview potential describe regulatory mechanisms. In addition, discuss recently described mechanistic basis oncogenic function. Finally, speculate on novel approaches that take into account subcellular compartmentalization outline new research directions would contribute better understanding fundamental roles health disease.

Язык: Английский

Процитировано

6
PARP1 UFMylation ensures the stability of stalled replication forks DOI Creative Commons

Yamin Gong,

Zhifeng Wang,

Wen Zong

и другие.

Proceedings of the National Academy of Sciences, Год журнала: 2024, Номер 121(18)

Опубликована: Апрель 24, 2024

The S-phase checkpoint involving CHK1 is essential for fork stability in response to stalling. PARP1 acts as a sensor of replication stress and required activation. However, it unclear how the activity regulated. Here, we found that UFMylation efficient activation by UFMylating at K548 during stress. Inactivation UFL1, E3 enzyme UFMylation, delayed inhibits nascent DNA degradation blockage seen PARP1-deficient cells. An vitro study indicated UFMylated K548, which enhances its catalytic activity. Correspondingly, UFMylation-deficient mutant (K548R) pathogenic (F553L) compromised activation, restart stalled forks following blockage, chromosome stability. Defective also resulted excessive forks. Finally, observed knock-in mice exhibited increased sensitivity caused anticancer treatments. Thus, demonstrate promotes stress, thus safeguarding genome integrity.

Язык: Английский

Процитировано

6
HPF1 Regulates Pol β Efficiency in Nucleosomes via the Modulation of Total Poly(ADP-Ribose) Synthesis DOI Open Access
Mikhail M. Kutuzov, Dinara Sayfullina, E. A. Belousova

и другие.

International Journal of Molecular Sciences, Год журнала: 2025, Номер 26(5), С. 1794 - 1794

Опубликована: Фев. 20, 2025

The maintenance of genome stability and the prevention genotoxic damage to DNA require immediate repair. In cell, repair process is usually preceded by a release from complexes with chromatin proteins accompanied nucleosome sliding, relaxing or disassembly. Base excision (BER) corrects most common lesions, which does not disturb helix dramatically. Notably, small lesions can be repaired in without global decompaction. One regulatory mechanisms poly(ADP-ribosyl)ation, leading relaxation nucleosome. our work, we demonstrated that recently discovered protein, HPF1, modulate efficiency one key BER stages-DNA synthesis-via regulation total poly(ADP-ribosyl)ation. Accordingly, investigated both short-patch long-patch synthesis catalyzed polymerase β (pol β; main BER) showed HPF1's influence on poly(ADP-ribosyl)ation PARP1 especially PARP2 results more efficient case pathway nucleosomes. Additionally, HPF1-dependent was found positively regulate BER.

Язык: Английский

Процитировано

0
Regulation of transcription patterns, poly(ADP-ribose), and RNA-DNA hybrids by the ATM protein kinase DOI Creative Commons
Phillip R. Woolley, Xuemei Wen, Olivia M. Conway

и другие.

Cell Reports, Год журнала: 2024, Номер 43(3), С. 113896 - 113896

Опубликована: Март 1, 2024

The ataxia telangiectasia mutated (ATM) protein kinase is a master regulator of the DNA damage response and also an important sensor oxidative stress. Analysis gene expression in ataxia-telangiectasia (A-T) patient brain tissue shows that large-scale transcriptional changes occur cerebellum correlate with level guanine-cytosine (GC) content transcribed genes. In human neuron-like cells culture, we map locations poly(ADP-ribose) RNA-DNA hybrid accumulation genome-wide ATM inhibition find these marks coincide high transcription levels, active histone marks, GC content. Antioxidant treatment reverses R-loops regions, consistent central role reactive oxygen species promoting lesions. Based on results, postulate transcription-associated lesions accumulate ATM-deficient single-strand breaks PARylation at sites ultimately generate compromise function lead to neurodegeneration over time A-T patients.

Язык: Английский

Процитировано

4