DNA replication stress: oncogenes in the spotlight

Primo, Luiza M. F.; Teixeira, Leonardo K.

doi:10.1590/1678-4685gmb-2019-0138

Cited by 36 publications

(18 citation statements)

References 145 publications

(214 reference statements)

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“…MDM2 transgenic mice also showed increased chromosome breaks, chromosome fusions, aneuploidy, and polyploidy (Lushnikova et al, 2011). It has also been shown that p53 disruption by MDM2 overexpression activates the intra S-phase checkpoint to inhibit DNA replication origin firing, causing replication fork instability (Frum et al, 2014;Primo and Teixeira, 2019).…”

Section: Mdm2 Affects Genomic Instability In P53-dependent Mannermentioning

confidence: 99%

Targeting Mouse Double Minute 2: Current Concepts in DNA Damage Repair and Therapeutic Approaches in Cancer

Peng

Lang

et al. 2020

Front. Pharmacol.

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Defects in DNA damage repair may cause genome instability and cancer development. The tumor suppressor gene p53 regulates cell cycle arrest to allow time for DNA repair. The oncoprotein mouse double minute 2 (MDM2) promotes cell survival, proliferation, invasion, and therapeutic resistance in many types of cancer. The major role of MDM2 is to inhibit p53 activity and promote its degradation. In this review, we describe the influence of MDM2 on genomic instability, the role of MDM2 on releasing p53 and binding DNA repair proteins to inhibit repair, and the regulation network of MDM2 including its transcriptional modifications, protein stability, and localization following DNA damage in genome integrity maintenance and in MDM2-p53 axis control. We also discuss p53-dependent and p53 independent oncogenic function of MDM2 and the outcomes of clinical trials that have been used with clinical inhibitors targeting p53-MDM2 to treat certain cancers.

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Section: Mdm2 Affects Genomic Instability In P53-dependent Mannermentioning

confidence: 99%

Targeting Mouse Double Minute 2: Current Concepts in DNA Damage Repair and Therapeutic Approaches in Cancer

Peng

Lang

et al. 2020

Front. Pharmacol.

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“…Oncogene activation, another hallmark of cancer, may interfere with normal cell proliferation and DNA replication. In fact, certain oncogenes are able to induce replication stress and promote genomic instability in human carcinogenesis ( Primo and Teixeira, 2019 ). One such example is oncogenic Cyclin E/CDK2 complex.…”

Section: Cyclin E/cdk2-induced Replication Stress Causes Genomic Instability In Human Cancersmentioning

confidence: 99%

Cyclin E/CDK2: DNA Replication, Replication Stress and Genomic Instability

Fagundes

Teixeira

2021

Front. Cell Dev. Biol.

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DNA replication must be precisely controlled in order to maintain genome stability. Transition through cell cycle phases is regulated by a family of Cyclin-Dependent Kinases (CDKs) in association with respective cyclin regulatory subunits. In normal cell cycles, E-type cyclins (Cyclin E1 and Cyclin E2, CCNE1 and CCNE2 genes) associate with CDK2 to promote G1/S transition. Cyclin E/CDK2 complex mostly controls cell cycle progression and DNA replication through phosphorylation of specific substrates. Oncogenic activation of Cyclin E/CDK2 complex impairs normal DNA replication, causing replication stress and DNA damage. As a consequence, Cyclin E/CDK2-induced replication stress leads to genomic instability and contributes to human carcinogenesis. In this review, we focus on the main functions of Cyclin E/CDK2 complex in normal DNA replication and the molecular mechanisms by which oncogenic activation of Cyclin E/CDK2 causes replication stress and genomic instability in human cancer.

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“…These mutations include activating mutations in BRAF, RAS (KRAS and HRAS), and PTPN11 (78), which encodes the tyrosine phosphatase SHP-2, and inactivating mutations in the NF1 tumor suppressor gene (91), a negative regulator of RAS (92). Activation of the RAS signaling pathway leads to replication stress by driving DNA replication, by a similar mechanism to MYCN overexpression (93,94). (17).…”

Section: Alk and Map Kinase Pathwaysmentioning

confidence: 99%

Targeting the DNA Damage Response for the Treatment of High Risk Neuroblastoma

et al. 2020

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Despite intensive multimodal therapy, the survival rate for high risk neuroblastoma (HR-NB) remains <50%. Most cases initially respond to treatment but almost half will subsequently relapse with aggressive treatment resistant disease. Novel treatments exploiting the molecular pathology of NB and/or overcoming resistance to current genotoxic therapies are needed before survival rates can significantly improve. DNA damage response (DDR) defects are frequently observed in HR-NB including allelic deletion and loss of function mutations in key DDR genes, oncogene induced replication stress and cell cycle checkpoint dysfunction. Exploiting defects in the DDR has been a successful treatment strategy in some adult cancers. Here we review the genetic features of HR-NB which lead to DDR defects and the emerging molecular targeting agents to exploit them.

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DNA replication stress: oncogenes in the spotlight

Cited by 36 publications

References 145 publications

Targeting Mouse Double Minute 2: Current Concepts in DNA Damage Repair and Therapeutic Approaches in Cancer

Targeting Mouse Double Minute 2: Current Concepts in DNA Damage Repair and Therapeutic Approaches in Cancer

Cyclin E/CDK2: DNA Replication, Replication Stress and Genomic Instability

Targeting the DNA Damage Response for the Treatment of High Risk Neuroblastoma

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