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1.
Nat Commun ; 15(1): 2857, 2024 Apr 02.
Artículo en Inglés | MEDLINE | ID: mdl-38565848

RESUMEN

PARP2 is a DNA-dependent ADP-ribosyl transferase (ARTs) enzyme with Poly(ADP-ribosyl)ation activity that is triggered by DNA breaks. It plays a role in the Base Excision Repair pathway, where it has overlapping functions with PARP1. However, additional roles for PARP2 have emerged in the response of cells to replication stress. In this study, we demonstrate that PARP2 promotes replication stress-induced telomere fragility and prevents telomere loss following chronic induction of oxidative DNA lesions and BLM helicase depletion. Telomere fragility results from the activity of the break-induced replication pathway (BIR). During this process, PARP2 promotes DNA end resection, strand invasion and BIR-dependent mitotic DNA synthesis by orchestrating POLD3 recruitment and activity. Our study has identified a role for PARP2 in the response to replication stress. This finding may lead to the development of therapeutic approaches that target DNA-dependent ART enzymes, particularly in cancer cells with high levels of replication stress.


Asunto(s)
Reparación del ADN , ADN , Poli(ADP-Ribosa) Polimerasa-1/genética , Poli(ADP-Ribosa) Polimerasa-1/metabolismo , ADN/metabolismo , Daño del ADN , ADN Helicasas/genética , ADN Helicasas/metabolismo , Telómero/genética , Telómero/metabolismo
2.
J Mol Biol ; 436(1): 168207, 2024 01 01.
Artículo en Inglés | MEDLINE | ID: mdl-37481154

RESUMEN

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


Asunto(s)
ADN Cruciforme , Inestabilidad Genómica , Poli(ADP-Ribosa) Polimerasa-1 , Humanos , ADN/química , Reparación del ADN , Regulación de la Expresión Génica , Poli(ADP-Ribosa) Polimerasa-1/genética , Poli(ADP-Ribosa) Polimerasa-1/metabolismo , Ribosa/química , Animales
3.
Nucleic Acids Res ; 51(5): 2215-2237, 2023 03 21.
Artículo en Inglés | MEDLINE | ID: mdl-36794853

RESUMEN

PARP1 is a DNA-dependent ADP-Ribose transferase with ADP-ribosylation activity that is triggered by DNA breaks and non-B DNA structures to mediate their resolution. PARP1 was also recently identified as a component of the R-loop-associated protein-protein interaction network, suggesting a potential role for PARP1 in resolving this structure. R-loops are three-stranded nucleic acid structures that consist of a RNA-DNA hybrid and a displaced non-template DNA strand. R-loops are involved in crucial physiological processes but can also be a source of genome instability if persistently unresolved. In this study, we demonstrate that PARP1 binds R-loops in vitro and associates with R-loop formation sites in cells which activates its ADP-ribosylation activity. Conversely, PARP1 inhibition or genetic depletion causes an accumulation of unresolved R-loops which promotes genomic instability. Our study reveals that PARP1 is a novel sensor for R-loops and highlights that PARP1 is a suppressor of R-loop-associated genomic instability.


Asunto(s)
Inestabilidad Genómica , Poli(ADP-Ribosa) Polimerasa-1 , Estructuras R-Loop , Humanos , ADN/química , Reparación del ADN , Poli(ADP-Ribosa) Polimerasa-1/genética , Poli(ADP-Ribosa) Polimerasa-1/metabolismo , ARN/química
4.
Cell Mol Life Sci ; 79(4): 215, 2022 Mar 29.
Artículo en Inglés | MEDLINE | ID: mdl-35348914

RESUMEN

The ADP-ribose transferase (ART) family comprises 17 enzymes that catalyze mono- or poly-ADP-ribosylation, a post-translational modification of proteins. Present in all subcellular compartments, ARTs are implicated in a growing number of biological processes including DNA repair, replication, transcription regulation, intra- and extra-cellular signaling, viral infection and cell death. Five members of the family, PARP1, PARP2, PARP3, tankyrase 1 and tankyrase 2 are mainly described for their crucial functions in the maintenance of genome stability. It is well established that the most describedrole of PARP1, 2 and 3 is the repair of DNA lesions while tankyrases 1 and 2 are crucial for maintaining the integrity of telomeres. Telomeres, nucleoprotein complexes located at the ends of eukaryotic chromosomes, utilize their unique structure and associated set of proteins to orchestrate the mechanisms necessary for their own protection and replication. While the functions of tankyrases 1 and 2 at telomeres are well known, several studies have also brought PARP1, 2 and 3 to the forefront of telomere protection. The singular quality of the telomeric environment has highlighted protein interactions and molecular pathways distinct from those described throughout the genome. The aim of this review is to provide an overview of the current knowledge on the multiple roles of PARP1, PARP2, PARP3, tankyrase 1 and tankyrase 2 in the maintenance and preservation of telomere integrity.


Asunto(s)
ADP Ribosa Transferasas , Telómero , ADP Ribosa Transferasas/metabolismo , Adenosina Difosfato Ribosa/metabolismo , Reparación del ADN , Inestabilidad Genómica , Humanos , Telómero/genética , Telómero/metabolismo
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