PARP inhibition impedes the maturation of nascent DNA strands during DNA replication

Vaitsiankova, Alina; Burdová, Kamila; Sobol, Margarita; Gautam, Amit; Benada, Oldřich; Hanzlíková, Hana; Caldecott, Keith W.

doi:10.1038/s41594-022-00747-1

Cited by 74 publications

(58 citation statements)

References 57 publications

(74 reference statements)

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“…Later studies showed the role of PARP1 in NER ( Pines et al, 2012 ) ( Robu et al, 2013 ), cNHEJ ( Luijsterburg et al, 2016 ) and aNHEJ ( Mansour et al, 2010 ), microhomology-mediated end joining (MMEJ) ( Dutta et al, 2017 ), HR ( Hochegger et al, 2006 ) ( Hu et al, 2014 ), MMR ( Liu et al, 2011 ), and maintenance of replication fork stability ( Ronson et al, 2018 ) ( Yang et al, 2004 ). Notably, recent publications point out the connection between PARP1 and Okazaki fragments ( Hanzlikova et al, 2018 ) ( Vaitsiankova et al, 2022 ).…”

Section: Parp1 In Dna Repairmentioning

confidence: 99%

The potential of PARP inhibitors in targeted cancer therapy and immunotherapy

Hunia

Gawalski

Szredzka

et al. 2022

Front. Mol. Biosci.

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DNA damage response (DDR) deficiencies result in genome instability, which is one of the hallmarks of cancer. Poly (ADP-ribose) polymerase (PARP) enzymes take part in various DDR pathways, determining cell fate in the wake of DNA damage. PARPs are readily druggable and PARP inhibitors (PARPi) against the main DDR-associated PARPs, PARP1 and PARP2, are currently approved for the treatment of a range of tumor types. Inhibition of efficient PARP1/2-dependent DDR is fatal for tumor cells with homologous recombination deficiencies (HRD), especially defects in breast cancer type 1 susceptibility protein 1 or 2 (BRCA1/2)-dependent pathway, while allowing healthy cells to survive. Moreover, PARPi indirectly influence the tumor microenvironment by increasing genomic instability, immune pathway activation and PD-L1 expression on cancer cells. For this reason, PARPi might enhance sensitivity to immune checkpoint inhibitors (ICIs), such as anti-PD-(L)1 or anti-CTLA4, providing a rationale for PARPi-ICI combination therapies. In this review, we discuss the complex background of the different roles of PARP1/2 in the cell and summarize the basics of how PARPi work from bench to bedside. Furthermore, we detail the early data of ongoing clinical trials indicating the synergistic effect of PARPi and ICIs. We also introduce the diagnostic tools for therapy development and discuss the future perspectives and limitations of this approach.

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Section: Parp1 In Dna Repairmentioning

confidence: 99%

The potential of PARP inhibitors in targeted cancer therapy and immunotherapy

Hunia

Gawalski

Szredzka

et al. 2022

Front. Mol. Biosci.

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“…Members of the PARP family, and specifically PARP1, signal DNA single‐strand breaks thus activating the repair of these lesions. More recently, PARP1 has also been implicated in the repair of Okazaki fragments that occur during discontinuous DNA replication, since these fragments in essence resemble DNA single‐strand breaks [ 5 ]. By removing the functions of both BRCA1/2 and PARP, cells accumulate elevated levels of DNA damage, leading to cell death.…”

Section: Synthetic Interactionsmentioning

confidence: 99%

Exploring the genetic space of the DNA damage response for cancer therapy through CRISPR‐based screens

Wilson

Loizou

2022

Molecular Oncology

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The concepts of synthetic lethality and viability have emerged as powerful approaches to identify vulnerabilities and resistances within the DNA damage response for the treatment of cancer. Historically, interactions between two genes have had a longstanding presence in genetics and have been identified through forward genetic screens that rely on the molecular basis of the characterized phenotypes, typically caused by mutations in single genes. While such complex genetic interactions between genes have been studied extensively in model organisms, they have only recently been prioritized as therapeutic strategies due to technological advancements in genetic screens. Here, we discuss synthetic lethal and viable interactions within the DNA damage response and present how CRISPR-based genetic screens and chemical compounds have allowed for the systematic identification and targeting of such interactions for the treatment of cancer.

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“…Preclinical experiments demonstrated that inhibition of PARP activity renders cells susceptible to carcinogenic agents [ 29 ], suggesting that inhibition of the PARP protein has a role in carcinogenesis. Indeed, inhibition of PARP impedes the maturation of nascent DNA strands during DNA replication [ 30 ]. This brings about the production of double-strand breaks and stalled replication forks.…”

Section: Brca 1/2 Pathogenic Mutationsmentioning

confidence: 99%

PARP Inhibition and Beyond in BRCA-Associated Breast Cancer in Women: A State-Of-The-Art Summary of Preclinical Research on Risk Reduction and Clinical Benefits

Pauwels

Bourguignon

2022

Med Princ Pract

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In mammalian cells, DNA damage response initiates repair by error-free homologous recombination (HRR) or by error-prone non-homogeneous end joining (NHEJ). DNA damage is detected by PARP proteins that facilitate this repair, both in normal cells and in cancer cells. Cells that contain BRCA1/2 mutations have an HRR deficient repair mechanism which may result in unrepaired one-ended double-strand breaks and stalled replication forks, considered as the most lethal cell damage. Here we review the state of the art of the role of Poly (ADP-ribose) polymerase (PARP) inhibitors as a precision targeted anticancer drug in BRCA1/2 mutated female breast cancer. The main role of the archetype PARP1 in the cell nucleus is to detect and adhere to single-strand breaks. This mediates the damage repair, after which cells-including cancer cells-may continue replication. This process is called synthetic lethality. As for PARP monotherapy, progression free survival has been observed using the FDA and EMA approved drugs olaparib and talazoparib. In the case of combined drug therapy, a synergy between veliparib and platinum drugs has been demonstrated. Information regarding adverse effects is limited, but consistently, hematological effects have been described. However, there is need for multicenter trials, preferably conducted without commercial guidance and funding. Some of the available trial results mention resistance to PARP inhibitors. In this review we also describe the various causes of PARP inhibitor resistance as well as the research that indicates how to overcome this phenomenon.

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PARP inhibition impedes the maturation of nascent DNA strands during DNA replication

Cited by 74 publications

References 57 publications

The potential of PARP inhibitors in targeted cancer therapy and immunotherapy

The potential of PARP inhibitors in targeted cancer therapy and immunotherapy

Exploring the genetic space of the DNA damage response for cancer therapy through CRISPR‐based screens

PARP Inhibition and Beyond in BRCA-Associated Breast Cancer in Women: A State-Of-The-Art Summary of Preclinical Research on Risk Reduction and Clinical Benefits

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