Multifaceted Role of PARP1 in Maintaining Genome Stability Through Its Binding to Alternative DNA Structures

Laspata, Natalie; Muoio, Daniela; Fouquerel, Elise

doi:10.1016/j.jmb.2023.168207

Cited by 12 publications

(5 citation statements)

References 146 publications

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“…Instead, our findings reveal that a FANCJ-MLH1 interaction counters MSH2-bound G4s that sequester and restrict PARP1 S phase activation. Consistent with this model, FANCJ deficient cells have elevated G4s, that are substrates for PARP1 and MSH2 [26][27][28][29][30][31][32][33] , and correspondingly greater proximity between G4s and PARP1. Moreover, MSH2-deficient cells display more G4s and PARP1 activity compared to MSH2 proficient cells, which showed reduced PARP1 S phase activity and targetability.…”

Section: Discussionsupporting

confidence: 52%

“…FANCJ loss limits PARP1 activity which along with PARP1 trapping is thought to underlie the toxicity of PARPi. Thus, we sought to understand if PARP1 bound to G4s 28 “G4-sequestered PARP1” was similar to canonical trapped PARP1 induced by PARPi ( Fig. 5a ).…”

Section: Resultsmentioning

confidence: 99%

“…Given that PARP1 binds G4s 28 and is distinct from trapped PARP1, we sought to determine if this insight could be leveraged to clarify how PARPi is toxic in BRCA1 deficient cells. Indeed, PARP1 sequestering that limits PARP1 replication activity could be toxic in settings in which this PARP1 activity is essential.…”

Section: Resultsmentioning

confidence: 99%

“…Given that MMR and PARP1 bind G4 structures that form in the replisome of FANCJ deficient cells [26][27][28][29][30][31][32][33] , we sought to test if the proximity of PARP1 to G4s was also enhanced. First, we confirmed that the BG4 antibody detected greater signal in the RPE1 and U2OS FANCJ null cells as well as in WT cells following treatment with the G4 stabilizing agent, pyridostatin (PDS) (Supplementary Fig.…”

Section: Fancj Promotes Parp1 Activity During Dna Replication and Lim...mentioning

confidence: 99%

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FANCJ promotes PARP1 activity during DNA replication that is essential in BRCA1 deficient cells

Cong,

MacGilvary,

Lee

et al. 2024

Preprint

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Single-stranded DNA gaps are postulated to be fundamental to the mechanism of anti-cancer drugs. Gaining insights into their induction could therefore be pivotal for advancing therapeutic strategies. For poly (ADP-ribose) polymerase inhibitors (PARPi) to be effective, the presence of FANCJ helicase is required. However, the relationship between FANCJ dependent gaps and PARP1 catalytic inhibition or trapping-both linked to PARPi toxicity in BRCA deficient cells-is yet to be elucidated. Here, we find that the efficacy of PARPi is contingent on S-phase PARP1 activity, which is compromised in FANCJ deficient cells because PARP1, along with MSH2, is "sequestered" by G-quadruplexes. PARP1's replication activity is also diminished in cells missing a FANCJ-MLH1 interaction, but in such cells, depleting MSH2 can release sequestered PARP1, restoring PARPi-induced gaps and sensitivity. Our observations indicate that sequestered and trapped PARP1 are different chromatin-bound forms, with FANCJ loss increasing PARPi resistance in cells susceptible to canonical PARP1 trapping. However, in BRCA1 null cells, the loss of FANCJ mirrors the effects of PARP1 loss or inhibition, with the common detrimental factor being the loss of PARP1 activity during DNA replication, not trapping. These insights underline the crucial role of PARP1 activity during DNA replication in BRCA deficient cells and emphasize the importance of understanding drug mechanisms for enhancing precision medicine.

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Section: Discussionsupporting

confidence: 52%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Fancj Promotes Parp1 Activity During Dna Replication and Lim...mentioning

confidence: 99%

See 2 more Smart Citations

FANCJ promotes PARP1 activity during DNA replication that is essential in BRCA1 deficient cells

Cong,

MacGilvary,

Lee

et al. 2024

Preprint

View full text Add to dashboard Cite

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“…PARP1 generally binds to DNA damage sites and recruits relevant DNA damage repair factors to promote DNA damage repair and maintain gene stability. A recent study has shown that PARP1 can bind to alternative DNA structures to maintain genomic stability, including stagnant replication forks [18] and R loops [19]. The function of PARP2 overlaps with that of PARP1, and PARP2 is recruited to the site of damage and activated by PARP1, which subsequently catalyzes branching PARylation at the site of damage [20].…”

Section: Key Proteins Of Adp-ribosylation In Dna Repairmentioning

confidence: 99%

The Complex Network of ADP-Ribosylation and DNA Repair: Emerging Insights and Implications for Cancer Therapy

Li,

Luo,

Xie

2023

IJMS

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ADP-ribosylation is a post-translational modification of proteins that plays a key role in various cellular processes, including DNA repair. Recently, significant progress has been made in understanding the mechanism and function of ADP-ribosylation in DNA repair. ADP-ribosylation can regulate the recruitment and activity of DNA repair proteins by facilitating protein–protein interactions and regulating protein conformations. Moreover, ADP-ribosylation can influence additional post-translational modifications (PTMs) of proteins involved in DNA repair, such as ubiquitination, methylation, acetylation, phosphorylation, and SUMOylation. The interaction between ADP-ribosylation and these additional PTMs can fine-tune the activity of DNA repair proteins and ensure the proper execution of the DNA repair process. In addition, PARP inhibitors have been developed as a promising cancer therapeutic strategy by exploiting the dependence of certain cancer types on the PARP-mediated DNA repair pathway. In this paper, we review the progress of ADP-ribosylation in DNA repair, discuss the crosstalk of ADP-ribosylation with additional PTMs in DNA repair, and summarize the progress of PARP inhibitors in cancer therapy.

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Characterization of PARP1 binding to c-KIT1 G-quadruplex DNA: Insights into domain-specific interactions

Hanuman Singh,

Deeksha,

Rajakumara

2024

Biophysical Chemistry

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Multifaceted Role of PARP1 in Maintaining Genome Stability Through Its Binding to Alternative DNA Structures

Cited by 12 publications

References 146 publications

FANCJ promotes PARP1 activity during DNA replication that is essential in BRCA1 deficient cells

FANCJ promotes PARP1 activity during DNA replication that is essential in BRCA1 deficient cells

The Complex Network of ADP-Ribosylation and DNA Repair: Emerging Insights and Implications for Cancer Therapy

Characterization of PARP1 binding to c-KIT1 G-quadruplex DNA: Insights into domain-specific interactions

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