The PARP Way to Epigenetic Changes

Ummarino, Simone; Hausman, Clinton; Ruscio, Annalisa Di

doi:10.3390/genes12030446

Cited by 26 publications

(19 citation statements)

References 104 publications

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“…This process, known as poly(ADP-ribosyl)ation, produces one ADP-ribose and one nicotinamide for every NAD + molecule processed. The ADP-ribose unit is subsequently connected to carboxyl groups in the target protein structure by glutamate, aspartate, lysine, arginine and serine residues [27,85]. When poly(ADP-ribose) (PAR) accumulates, it features a strong negatively charged nucleic-acid-like structure [86] and neutralizes positively charged groups, mediating chromatin de-condensation and stimulating transcription [81].…”

Section: Poly(adp-ry)lation Of Dnmt1 Determines Dna Methylationmentioning

confidence: 99%

“…The activity of PARP1 is engaged in several biological and cellular functions, including histone or chromatin alterations and consequent gene expression modulation. However, the epigenetic mechanism of PARP1 differs from that of DNA methylation because it also enzymatically opens condensed chromatin in advance of transcriptional activity [27,28]. The current review expands on PARP1's potential importance as a new therapeutic target for clinical applications by expanding its numerous roles linked with DNA methylation in normal and cancer cells.…”

Section: Introductionmentioning

confidence: 97%

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DNA Methylation Malleability and Dysregulation in Cancer Progression: Understanding the Role of PARP1

Srivastava

Lodhi

2022

Biomolecules

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Mammalian genomic DNA methylation represents a key epigenetic modification and its dynamic regulation that fine-tunes the gene expression of multiple pathways during development. It maintains the gene expression of one generation of cells; particularly, the mitotic inheritance of gene-expression patterns makes it the key governing mechanism of epigenetic change to the next generation of cells. Convincing evidence from recent discoveries suggests that the dynamic regulation of DNA methylation is accomplished by the enzymatic action of TET dioxygenase, which oxidizes the methyl group of cytosine and activates transcription. As a result of aberrant DNA modifications, genes are improperly activated or inhibited in the inappropriate cellular context, contributing to a plethora of inheritable diseases, including cancer. We outline recent advancements in understanding how DNA modifications contribute to tumor suppressor gene silencing or oncogenic-gene stimulation, as well as dysregulation of DNA methylation in cancer progression. In addition, we emphasize the function of PARP1 enzymatic activity or inhibition in the maintenance of DNA methylation dysregulation. In the context of cancer remediation, the impact of DNA methylation and PARP1 pharmacological inhibitors, and their relevance as a combination therapy are highlighted.

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Section: Poly(adp-ry)lation Of Dnmt1 Determines Dna Methylationmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 97%

DNA Methylation Malleability and Dysregulation in Cancer Progression: Understanding the Role of PARP1

Srivastava

Lodhi

2022

Biomolecules

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“…To date, there are 24 identified KDMs in human cells, with some known or predicted to contain CC domains and many operating under the control of PARP1 activity. [117,[125][126][127][128] Intriguingly, the effect of PARP1 activity on KDMs can vary widely. For example, KDM5B, which also demethylates H3K4me3 and shares a high degree of sequence similarity with KDM5A, is negatively regulated by PARP1 activity during transcription.…”

Section: Therapeutic Targeting Of Kdm5a With Parp Inhibitors?mentioning

confidence: 99%

Joining the PARty: PARP Regulation of KDM5A during DNA Repair (and Transcription?)

2022

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The lysine demethylase KDM5A collaborates with PARP1 and the histone variant macroH2A1.2 to modulate chromatin to promote DNA repair. Indeed, KDM5A engages poly(ADP-ribose) (PAR) chains at damage sites through a previously uncharacterized coiled-coil domain, a novel binding mode for PAR interactions. While KDM5A is a well-known transcriptional regulator, its function in DNA repair is only now emerging.Here we review the molecular mechanisms that regulate this PARP1-macroH2A1.2-KDM5A axis in DNA damage and consider the potential involvement of this pathway in transcription regulation and cancer. Using KDM5A as an example, we discuss how multifunctional chromatin proteins transition between several DNA-based processes, which must be coordinated to protect the integrity of the genome and epigenome. The dysregulation of chromatin and loss of genome integrity that is prevalent in human diseases including cancer may be related and could provide opportunities to target multitasking proteins with these pathways as therapeutic strategies.

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“…PARylation, is an epigenetic PTM mark, and PAR code is involved in above process through chromatin remodeling, heterochromatin reorganization, histones exchange, etc. (68,69). Several DNA methyltransferases, histone lysine methyl-and acetyl-transferases have both writer and reader domains of corresponding epigenetic mark, and both reading and writing of the marks direct a particular epigenetic outcome (70)(71)(72).…”

Section: Parp1 Is Both Writer and Reader Of Par Codementioning

confidence: 99%

PAR recognition by PARP1 regulates DNA-dependent activities and independently stimulates catalytic activity of PARP1

Deeksha

Abhishek

Rajakumara

2021

Preprint

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Poly(ADP-ribosyl)ation is a post translational modification, predominantly catalyzed by Poly(ADP-ribose) polymerase 1 (PARP1) in response to DNA damage, mediating the DNA repair process to maintain genomic integrity. Single strand (SSB) and double strand (DSB) DNA breaks are bonafide stimulators of PARP1 activity. We identified that, in addition, single strand (ss) DNA also binds and stimulates the PARP1 activity. Poly(ADP-ribose) (PAR) is chemically similar to ssDNA. However, PAR mediated PARP1 regulation remains unexplored. Here, we report ZnF3, BRCT and WGR, hitherto uncharacterized, as PAR-specific reader domains of PARP1. Surprisingly, these domains recognize PARylated protein with a higher affinity compared to PAR, but do not bind to DNA. Conversely, N-terminal domains, ZnF1 and ZnF2, of PARP1 recognize DNA but not PAR. Further competition binding studies suggest that PAR binding, allosterically releases DNA from PARP1. Unexpectedly, PAR showed catalytic stimulation of PARP1 but hampers the DNA dependent stimulation. Altogether, our work discovers dedicated PAR and DNA reader domains of the PARP1, and uncovers a novel mechanism of allosteric stimulation of the catalytic activity of PARP1 but retardation of DNA-dependent activities of PARP1 by its catalytic product PAR.

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The PARP Way to Epigenetic Changes

Cited by 26 publications

References 104 publications

DNA Methylation Malleability and Dysregulation in Cancer Progression: Understanding the Role of PARP1

DNA Methylation Malleability and Dysregulation in Cancer Progression: Understanding the Role of PARP1

Joining the PARty: PARP Regulation of KDM5A during DNA Repair (and Transcription?)

PAR recognition by PARP1 regulates DNA-dependent activities and independently stimulates catalytic activity of PARP1

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