Inhibition of DNA Repair in Cancer Therapy: Toward a Multi-Target Approach

Alterations in DNA repair pathways are one of the main drivers of cancer insurgence. Nevertheless, cancer cells are more susceptible to DNA damage than normal cells and they rely on specific functional repair pathways to survive. Thanks to advances in genome sequencing, we now have a better idea of which genes are mutated in specific cancers and this prompted the development of inhibitors targeting DNA repair players involved in pathways essential for cancer cells survival. Currently, the pivotal concept is that combining the inhibition of mechanisms on which cancer cells viability depends is the most promising way to treat tumorigenesis. Numerous inhibitors have been developed and for many of them, efficacy has been demonstrated either alone or in combination with chemo or radiotherapy. In this review, we will analyze the principal pathways involved in cell cycle checkpoint and DNA repair focusing on how their alterations could predispose to cancer, then we will explore the inhibitors developed or in development specifically targeting different proteins involved in each pathway, underscoring the rationale behind their usage and how their combination and/or exploitation as adjuvants to classic therapies could help in patients clinical outcome.

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Cigarette smoke induces DNA damage and inhibits cell cycle checkpoint and DNA repair pathways

The FASEB Journal ◽

10.1096/fasebj.26.1_supplement.538.2 ◽

2012 ◽

Vol 26 (S1) ◽

Author(s):

Philip Thai ◽

Daniel Chen ◽

Reen Wu

Keyword(s):

Cell Cycle ◽

Dna Damage ◽

Dna Repair ◽

Cigarette Smoke ◽

Cell Cycle Checkpoint ◽

Cycle Checkpoint ◽

Repair Pathways

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WIP1 Promotes Homologous Recombination and Modulates Sensitivity to PARP Inhibitors

Cells ◽

10.3390/cells8101258 ◽

2019 ◽

Vol 8 (10) ◽

pp. 1258 ◽

Cited By ~ 5

Author(s):

Kamila Burdova ◽

Radka Storchova ◽

Matous Palek ◽

Libor Macurek

Keyword(s):

Dna Damage ◽

Dna Repair ◽

Homologous Recombination ◽

Cancer Cells ◽

Genotoxic Stress ◽

Parp Inhibitors ◽

Cell Cycle Checkpoint ◽

Dna Lesion ◽

Cycle Checkpoint ◽

G2 Cells

Genotoxic stress triggers a combined action of DNA repair and cell cycle checkpoint pathways. Protein phosphatase 2C delta (referred to as WIP1) is involved in timely inactivation of DNA damage response by suppressing function of p53 and other targets at chromatin. Here we show that WIP1 promotes DNA repair through homologous recombination. Loss or inhibition of WIP1 delayed disappearance of the ionizing radiation-induced 53BP1 foci in S/G2 cells and promoted cell death. We identify breast cancer associated protein 1 (BRCA1) as interactor and substrate of WIP1 and demonstrate that WIP1 activity is needed for correct dynamics of BRCA1 recruitment to chromatin flanking the DNA lesion. In addition, WIP1 dephosphorylates 53BP1 at Threonine 543 that was previously implicated in mediating interaction with RIF1. Finally, we report that inhibition of WIP1 allowed accumulation of DNA damage in S/G2 cells and increased sensitivity of cancer cells to a poly-(ADP-ribose) polymerase inhibitor olaparib. We propose that inhibition of WIP1 may increase sensitivity of BRCA1-proficient cancer cells to olaparib.

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Spermidine/spermine N1-acetyltransferase overexpression in kidney epithelial cells disrupts polyamine homeostasis, leads to DNA damage, and causes G2 arrest

AJP Cell Physiology ◽

10.1152/ajpcell.00451.2006 ◽

2007 ◽

Vol 292 (3) ◽

pp. C1204-C1215 ◽

Cited By ~ 37

Author(s):

Kamyar Zahedi ◽

John J. Bissler ◽

Zhaohui Wang ◽

Anuradha Josyula ◽

Lu Lu ◽

...

Keyword(s):

Cell Cycle ◽

Cell Proliferation ◽

Dna Damage ◽

Dna Repair ◽

Ischemia Reperfusion Injury ◽

Ischemia Reperfusion ◽

Dna Lesions ◽

Cell Cycle Checkpoint ◽

Cycle Checkpoint

Expression of spermidine/spermine N1-acetyltransferase (SSAT) increases in kidneys subjected to ischemia-reperfusion injury (IRI). Increased expression of SSAT in vitro leads to alterations in cellular polyamine content, depletion of cofactors and precursors of polyamine synthesis, and reduced cell proliferation. In our model system, a >28-fold increase in SSAT levels in HEK-293 cells leads to depletion of polyamines and elevation in the enzymatic activities of ornithine decarboxylase and S-adenosylmethionine decarboxylase, suggestive of a compensatory reaction to increased polyamine catabolism. Increased expression of SSAT also led to DNA damage and G2 arrest. The increased DNA damage was primarily due to the depletion of polyamines. Other factors such as increased production of H2O2 due to polyamine oxidase activity may play a secondary role in the induction of DNA lesions. In response to DNA damage the ATM/ATR → Chk1/2 DNA repair and cell cycle checkpoint pathways were activated, mediating the G2 arrest in SSAT-expressing cells. In addition, the activation of ERK1 and ERK2, which play integral roles in the G2/M transition, is impaired in cells expressing SSAT. These results indicate that the disruption of polyamine homeostasis due to enhanced SSAT activity leads to DNA damage and reduced cell proliferation via activation of DNA repair and cell cycle checkpoint and disruption of Raf → MEK → ERK pathways. We propose that in kidneys subjected to IRI, one mechanism through which increased expression of SSAT may cause cellular injury and organ damage is through induction of DNA damage and the disruption of cell cycle.

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Negative regulator of E2F transcription factors links cell cycle checkpoint and DNA damage repair

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1720094115 ◽

2018 ◽

Vol 115 (16) ◽

pp. E3837-E3845 ◽

Cited By ~ 13

Author(s):

Lili Wang ◽

Hanchen Chen ◽

Chongyang Wang ◽

Zhenjie Hu ◽

Shunping Yan

Keyword(s):

Cell Cycle ◽

Dna Damage ◽

Dna Repair ◽

Transcription Factors ◽

Genome Stability ◽

Cell Cycle Checkpoint ◽

Cell Cycle Checkpoints ◽

Negative Regulator ◽

Cycle Checkpoint ◽

E2f Transcription Factors

DNA damage poses a serious threat to genome integrity and greatly affects growth and development. To maintain genome stability, all organisms have evolved elaborate DNA damage response mechanisms including activation of cell cycle checkpoints and DNA repair. Here, we show that the DNA repair protein SNI1, a subunit of the evolutionally conserved SMC5/6 complex, directly links these two processes in Arabidopsis. SNI1 binds to the activation domains of E2F transcription factors, the key regulators of cell cycle progression, and represses their transcriptional activities. In turn, E2Fs activate the expression of SNI1, suggesting that E2Fs and SNI1 form a negative feedback loop. Genetically, overexpression of SNI1 suppresses the phenotypes of E2F-overexpressing plants, and loss of E2F function fully suppresses the sni1 mutant, indicating that SNI1 is necessary and sufficient to inhibit E2Fs. Altogether, our study revealed that SNI1 is a negative regulator of E2Fs and plays dual roles in DNA damage responses by linking cell cycle checkpoint and DNA repair.

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Exploiting replicative stress in gynecological cancers as a therapeutic strategy

International Journal of Gynecological Cancer ◽

10.1136/ijgc-2020-001277 ◽

2020 ◽

Vol 30 (8) ◽

pp. 1224-1238 ◽

Cited By ~ 1

Author(s):

Natalie YL Ngoi ◽

Vignesh Sundararajan ◽

David SP Tan

Keyword(s):

Cell Cycle ◽

Dna Damage ◽

Dna Repair ◽

Ataxia Telangiectasia ◽

Therapeutic Index ◽

Cell Cycle Checkpoint ◽

Mitotic Catastrophe ◽

Gynecological Cancers ◽

Replicative Stress ◽

Cycle Checkpoint

Elevated levels of replicative stress in gynecological cancers arising from uncontrolled oncogenic activation, loss of key tumor suppressors, and frequent defects in the DNA repair machinery are an intrinsic vulnerability for therapeutic exploitation. The presence of replication stress activates the DNA damage response and downstream checkpoint proteins including ataxia telangiectasia and Rad3 related kinase (ATR), checkpoint kinase 1 (CHK1), and WEE1-like protein kinase (WEE1), which trigger cell cycle arrest while protecting and restoring stalled replication forks. Strategies that increase replicative stress while lowering cell cycle checkpoint thresholds may allow unrepaired DNA damage to be inappropriately carried forward in replicating cells, leading to mitotic catastrophe and cell death. Moreover, the identification of fork protection as a key mechanism of resistance to chemo- and poly (ADP-ribose) polymerase inhibitor therapy in ovarian cancer further increases the priority that should be accorded to the development of strategies targeting replicative stress. Small molecule inhibitors designed to target the DNA damage sensors, such as inhibitors of ataxia telangiectasia-mutated (ATM), ATR, CHK1 and WEE1, impair smooth cell cycle modulation and disrupt efficient DNA repair, or a combination of the above, have demonstrated interesting monotherapy and combinatorial activity, including the potential to reverse drug resistance and have entered developmental pipelines. Yet unresolved challenges lie in balancing the toxicity profile of these drugs in order to achieve a suitable therapeutic index while maintaining clinical efficacy, and selective biomarkers are urgently required. Here we describe the premise for targeting of replicative stress in gynecological cancers and discuss the clinical advancement of this strategy.

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Circadian Rhythm of NER and ATR Pathways

Biomolecules ◽

10.3390/biom11050715 ◽

2021 ◽

Vol 11 (5) ◽

pp. 715

Author(s):

Tae-Hong Kang

Keyword(s):

Cell Cycle ◽

Dna Damage ◽

Dna Repair ◽

Circadian Rhythm ◽

Circadian Clock ◽

Uv Radiation ◽

Mammalian Cells ◽

Cell Cycle Checkpoint ◽

Dna Damage Responses ◽

Cycle Checkpoint

Genomic integrity is constantly insulted by solar ultraviolet (UV) radiation. Adaptative cellular mechanisms called DNA damage responses comprising DNA repair, cell cycle checkpoint, and apoptosis, are believed to be evolved to limit genomic instability according to the photoperiod during a day. As seen in many other key cellular metabolisms, genome surveillance mechanisms against genotoxic UV radiation are under the control of circadian clock systems, thereby exhibiting daily oscillations in their catalytic activities. Indeed, it has been demonstrated that nucleotide excision repair (NER), the sole DNA repair mechanism correcting UV-induced DNA photolesions, and ataxia–telangiectasia-mutated and Rad3-related (ATR)-mediated cell cycle checkpoint kinase are subjected to the robust control of the circadian clock. The molecular foundation for the circadian rhythm of UV-induced DNA damage responses in mammalian cells will be discussed.

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Faculty Opinions recommendation of Interplay between Ino80 and Swr1 chromatin remodeling enzymes regulates cell cycle checkpoint adaptation in response to DNA damage.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1048201.500117 ◽

2006 ◽

Author(s):

Tim Humphrey

Keyword(s):

Cell Cycle ◽

Dna Damage ◽

Chromatin Remodeling ◽

Cell Cycle Checkpoint ◽

Checkpoint Adaptation ◽

Cycle Checkpoint

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Acceleration or Brakes: Which Is Rational for Cell Cycle-Targeting Neuroblastoma Therapy?

Biomolecules ◽

10.3390/biom11050750 ◽

2021 ◽

Vol 11 (5) ◽

pp. 750

Author(s):

Kiyohiro Ando ◽

Akira Nakagawara

Keyword(s):

Cell Cycle ◽

Dna Damage ◽

Cell Cycle Progression ◽

Parp Inhibitors ◽

Cell Cycle Checkpoint ◽

Mitotic Catastrophe ◽

Malignant Neoplasms ◽

Checkpoint Kinases ◽

Molecular Features ◽

Cycle Checkpoint

Unrestrained proliferation is a common feature of malignant neoplasms. Targeting the cell cycle is a therapeutic strategy to prevent unlimited cell division. Recently developed rationales for these selective inhibitors can be subdivided into two categories with antithetical functionality. One applies a “brake” to the cell cycle to halt cell proliferation, such as with inhibitors of cell cycle kinases. The other “accelerates” the cell cycle to initiate replication/mitotic catastrophe, such as with inhibitors of cell cycle checkpoint kinases. The fate of cell cycle progression or arrest is tightly regulated by the presence of tolerable or excessive DNA damage, respectively. This suggests that there is compatibility between inhibitors of DNA repair kinases, such as PARP inhibitors, and inhibitors of cell cycle checkpoint kinases. In the present review, we explore alterations to the cell cycle that are concomitant with altered DNA damage repair machinery in unfavorable neuroblastomas, with respect to their unique genomic and molecular features. We highlight the vulnerabilities of these alterations that are attributable to the features of each. Based on the assessment, we offer possible therapeutic approaches for personalized medicine, which are seemingly antithetical, but both are promising strategies for targeting the altered cell cycle in unfavorable neuroblastomas.

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The Interactions of DNA Repair, Telomere Homeostasis, and p53 Mutational Status in Solid Cancers: Risk, Prognosis, and Prediction

Cancers ◽

10.3390/cancers13030479 ◽

2021 ◽

Vol 13 (3) ◽

pp. 479

Author(s):

Pavel Vodicka ◽

Ladislav Andera ◽

Alena Opattova ◽

Ludmila Vodickova

Keyword(s):

Cell Cycle ◽

Dna Damage ◽

Dna Repair ◽

Dna Lesions ◽

Cell Cycle Checkpoint ◽

Solid Cancer ◽

Genomic Integrity ◽

Repair Capacity ◽

Mutational Status ◽

Telomere Homeostasis

The disruption of genomic integrity due to the accumulation of various kinds of DNA damage, deficient DNA repair capacity, and telomere shortening constitute the hallmarks of malignant diseases. DNA damage response (DDR) is a signaling network to process DNA damage with importance for both cancer development and chemotherapy outcome. DDR represents the complex events that detect DNA lesions and activate signaling networks (cell cycle checkpoint induction, DNA repair, and induction of cell death). TP53, the guardian of the genome, governs the cell response, resulting in cell cycle arrest, DNA damage repair, apoptosis, and senescence. The mutational status of TP53 has an impact on DDR, and somatic mutations in this gene represent one of the critical events in human carcinogenesis. Telomere dysfunction in cells that lack p53-mediated surveillance of genomic integrity along with the involvement of DNA repair in telomeric DNA regions leads to genomic instability. While the role of individual players (DDR, telomere homeostasis, and TP53) in human cancers has attracted attention for some time, there is insufficient understanding of the interactions between these pathways. Since solid cancer is a complex and multifactorial disease with considerable inter- and intra-tumor heterogeneity, we mainly dedicated this review to the interactions of DNA repair, telomere homeostasis, and TP53 mutational status, in relation to (a) cancer risk, (b) cancer progression, and (c) cancer therapy.

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