Expanding functions of ADP-ribosylation in the maintenance of genome integrity

Martin-Hernandez, Kathline; Rodríguez-Vargas, José Manuel; Schreiber, Valérie; Dantzer, Françoise

doi:10.1016/j.semcdb.2016.09.009

Cited by 79 publications

(97 citation statements)

References 110 publications

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“…In addition to PARP1 and PARG, other members of the PARP family have also been implicated in DSB repair and replication fork stability, most notably PARP2, PARP3, PARP10, and PARP14 (Martin-Hernandez et al 2017), and may contribute to cellular phenotypes of PARP1/2 in-hibitors given that some of them exhibit weaker target specificity.…”

Section: Functions Of Parp1 and Parg In Dna Repair And Replication Fomentioning

confidence: 99%

PARP and PARG inhibitors in cancer treatment

2020

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Oxidative and replication stress underlie genomic instability of cancer cells. Amplifying genomic instability through radiotherapy and chemotherapy has been a powerful but nonselective means of killing cancer cells. Precision medicine has revolutionized cancer therapy by putting forth the concept of selective targeting of cancer cells. Poly(ADP-ribose) polymerase (PARP) inhibitors represent a successful example of precision medicine as the first drugs targeting DNA damage response to have entered the clinic. PARP inhibitors act through synthetic lethality with mutations in DNA repair genes and were approved for the treatment of BRCA mutated ovarian and breast cancer. PARP inhibitors destabilize replication forks through PARP DNA entrapment and induce cell death through replication stress-induced mitotic catastrophe. Inhibitors of poly(ADP-ribose) glycohydrolase (PARG) exploit and exacerbate replication deficiencies of cancer cells and may complement PARP inhibitors in targeting a broad range of cancer types with different sources of genomic instability. Here I provide an overview of the molecular mechanisms and cellular consequences of PARP and PARG inhibition. I highlight clinical performance of four PARP inhibitors used in cancer therapy (olaparib, rucaparib, niraparib, and talazoparib) and discuss the predictive biomarkers of inhibitor sensitivity, mechanisms of resistance as well as the means of overcoming them through combination therapy.

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Section: Functions Of Parp1 and Parg In Dna Repair And Replication Fomentioning

confidence: 99%

PARP and PARG inhibitors in cancer treatment

2020

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“…The replicative stress response should ensure the identification and signalling of single strand breaks for its processing. PARP1 (a poly-ADP ribose polymerase) plays a multifaceted role in the cellular response to DNA damage, with evidences for involvement in multiple pathways of DNA damage repair and genome maintenance (for review: [115,116]). The existing roles of PARP1 within repair pathways are detection of DNA damage, poly(ADP-ribose) mediated recruitment of repair factors, and in poly(ADP-ribose) mediated regulation of biochemical activities.…”

Section: Poly-adp Ribose Polymerase (Parp1)mentioning

confidence: 99%

Replication Stress, DNA Damage, Inflammatory Cytokines and Innate Immune Response

Ragu

Matos-Rodrigues

Lopez

2020

Genes

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Complete and accurate DNA replication is essential to genome stability maintenance during cellular division. However, cells are routinely challenged by endogenous as well as exogenous agents that threaten DNA stability. DNA breaks and the activation of the DNA damage response (DDR) arising from endogenous replication stress have been observed at pre-or early stages of oncogenesis and senescence. Proper detection and signalling of DNA damage are essential for the autonomous cellular response in which the DDR regulates cell cycle progression and controls the repair machinery. In addition to this autonomous cellular response, replicative stress changes the cellular microenvironment, activating the innate immune response that enables the organism to protect itself against the proliferation of damaged cells. Thereby, the recent descriptions of the mechanisms of the pro-inflammatory response activation after replication stress, DNA damage and DDR defects constitute important conceptual novelties. Here, we review the links of replication, DNA damage and DDR defects to innate immunity activation by pro-inflammatory paracrine effects, highlighting the implications for human syndromes and immunotherapies.Genes 2020, 11, 409 2 of 26 formed when nascent transcripts re-anneal to their template DNA, displacing the non-template strand as single-stranded DNA (ssDNA) [12]. Elevated R-loop levels cause DNA damage and genome instability. The loss of RNA processing and regulatory factors increases R-loop levels, causing R-loop dependent DNA damage in eukaryotic cells [13][14][15][16].DNA breaks and activation of the DNA damage response (DDR), arising from endogenous replication stress, have been observed at early or precancerous stages, and adaptation to replication stress plays an important role in tumour development [17][18][19][20]. The DDR protects genome stability through the precise coordination of a network of pathways, ensuring faithful transmission of genetic material, including DNA replication, repair and recombination, cell cycle checkpoint and chromosome segregation. Ultimately, these autonomous cell responses induce senescence or cell death [21][22][23][24][25]. All these processes prevent the proliferation of cells bearing DNA damage and/or genetic rearrangements. In agreement, syndromes caused by mutations in DDR and/or DNA repair factors are often associated with high genetic instability, cancer predisposition and premature ageing [24,[26][27][28]. In addition to these cell-autonomous responses, protective process(es) also act at the organism level. Such mechanism(s) involve the modification of the cellular microenvironment and ultimately the activation of innate immunity.The inflammatory response is a universal cell-intrinsic response to infections or tissue damage. Inflammation, which is triggered when innate immune cells detect infection, for example, eliminates the initial cause of cell injury, clears out necrotic cells and tissues damaged from the original insult and from the inflammatory process, and initiates ...

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“…Nucleotides, the building blocks of nucleic acids, are emerging as the basis of important regulatory PTMs as well. Together with adenylylation (1) (also called AMPylation), ADP-ribosylation (ADPr) is the best-characterized nucleotide-based PTM and is especially known for its role in DNA repair signaling and as a target in cancer therapy (2–5). Though enzymatic conjugation of a PTM is usually limited to amino acids with similar functional groups (for example phosphorylation of hydroxyl groups on serine, threonine and tyrosine in eukaryotes), almost all chemically reactive amino acid side-chains have been reported to be ADP-ribosylated (6) with glutamate, aspartate, lysine and arginine historically considered as the main targets (7–14).…”

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confidence: 99%

Mass spectrometry for serine ADP-ribosylation? Think o-glycosylation!

Bonfiglio

Colby

Matić

2017

Nucleic Acids Research

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Protein ADP-ribosylation (ADPr), a biologically and clinically important post-translational modification, exerts its functions by targeting a variety of different amino acids. Its repertoire recently expanded to include serine ADPr, which is emerging as an important and widespread signal in the DNA damage response. Chemically, serine ADPr (and more generally o-glycosidic ADPr) is a form of o-glycosylation, and its extreme lability renders it practically invisible to standard mass spectrometry approaches, often leading to erroneous localizations. The knowledge from the mature field of o-glycosation and our own initial difficulties with mass spectrometric analyzes of serine ADPr suggest how to avoid these misidentifications and fully explore the scope of o-glycosidic ADPr in DNA damage response and beyond.

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Expanding functions of ADP-ribosylation in the maintenance of genome integrity

Cited by 79 publications

References 110 publications

PARP and PARG inhibitors in cancer treatment

PARP and PARG inhibitors in cancer treatment

Replication Stress, DNA Damage, Inflammatory Cytokines and Innate Immune Response

Mass spectrometry for serine ADP-ribosylation? Think o-glycosylation!

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