Origin of Genome Instability and Determinants of Mutational Landscape in Cancer Cells

Mehrotra, Sonam; Mittra, Indraneel

doi:10.3390/genes11091101

Cited by 10 publications

(6 citation statements)

References 87 publications

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“…This may occur not only because pro-inflammatory and oncogenic pathways often overlap but also because inflammation induces tissue damage and repair attempts and is interconnected with the production of high levels of ROS. These molecules are able to promote genomic instability that may increase the probability that onco-suppressors, such as, for example, p53, or proteins involved in DNA damage repair pathways, such as BRCA1, undergo loss-of-function mutations [ 45 ]. In the present study, we found that HHV-6A was able to infect BCPAP, a cell line derived from well-differentiated papillary thyroid carcinoma (PTC), the most benign form of thyroid cancer, and induce several effects that could favor progression towards more aggressive forms of thyroid cancers such as FTC or ATC.…”

Section: Discussionmentioning

confidence: 99%

HHV-6A Infection of Papillary Thyroid Cancer Cells Induces Several Effects Related to Cancer Progression

Mardente,

Romeo,

Asquino

et al. 2023

Viruses

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Recent studies have shown that thyrocytes are permissive to HHV-6A infection and that the virus may contribute to the pathogenesis of autoimmune thyroiditis. Thyroid autoimmune diseases increase the risk of papillary cancer, which is not surprising considering that chronic inflammation activates pathways that are also pro-oncogenic. Moreover, in this condition, cell proliferation is stimulated as an attempt to repair tissue damage caused by the inflammatory process. Interestingly, it has been reported that the well-differentiated papillary thyroid carcinoma (PTC), the less aggressive form of thyroid tumor, may progress to the more aggressive follicular thyroid carcinoma (FTC) and eventually to the anaplastic thyroid carcinoma (ATC), and that to such progression contributes the presence of an inflammatory/immune suppressive tumor microenvironment. In this study, we investigated whether papillary tumor cells (BCPAP) could be infected by human herpes virus-6A (HHV-6A), and if viral infection could induce effects related to cancer progression. We found that the virus dysregulated the expression of several microRNAs, such as miR155, miR9, and the miR221/222 cluster, which are involved in different steps of carcinogenesis, and increased the secretion of pro-inflammatory cytokines, particularly IL-6, which may also sustain thyroid tumor cell growth and promote cancer progression. Genomic instability and the expression of PTEN, reported to act as an oncogene in mutp53-carrying cells such as BCPAP, also increased following HHV-6A-infection. These findings suggest that a ubiquitous herpesvirus such as HHV-6A, which displays a marked tropism for thyrocytes, could be involved in the progression of PTC towards more aggressive forms of thyroid tumor.

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Section: Discussionmentioning

confidence: 99%

HHV-6A Infection of Papillary Thyroid Cancer Cells Induces Several Effects Related to Cancer Progression

Mardente,

Romeo,

Asquino

et al. 2023

Viruses

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“…Deregulated DNA synthesis has been linked to human diseases including cancer 14 – 16 . Indeed, a subset of RECQ4 clinical mutations are tumorigenic 3 , making RECQ4 an ideal candidate to study the contribution of DNA synthesis dysfunction to tumorigenesis.…”

Section: Introductionmentioning

confidence: 99%

DNA replication initiation factor RECQ4 possesses a role in antagonizing DNA replication initiation

Chang

et al. 2023

Nat Commun

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Deletion of the conserved C-terminus of the Rothmund-Thomson syndrome helicase RECQ4 is highly tumorigenic. However, while the RECQ4 N-terminus is known to facilitate DNA replication initiation, the function of its C-terminus remains unclear. Using an unbiased proteomic approach, we identify an interaction between the RECQ4 N-terminus and the anaphase-promoting complex/cyclosome (APC/C) on human chromatin. We further show that this interaction stabilizes APC/C co-activator CDH1 and enhances APC/C-dependent degradation of the replication inhibitor Geminin, allowing replication factors to accumulate on chromatin. In contrast, the function is blocked by the RECQ4 C-terminus, which binds to protein inhibitors of APC/C. A cancer-prone, C-terminal-deleted RECQ4 mutation increases origin firing frequency, accelerates G1/S transition, and supports abnormally high DNA content. Our study reveals a role of the human RECQ4 C-terminus in antagonizing its N-terminus, thereby suppressing replication initiation, and this suppression is impaired by oncogenic mutations.

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“…Genomic instability, one of the most prevalent features of human cancers, can cause cells to exhibit the cancer phenotype through mutations in oncogenes and cancer suppressor genes (3). Persistent genomic instability allows cancer cells to survive under selective pressure and adapt to their microenvironment by evolving to resist different therapies (4), and affects patient prognoses (5). Although genomic instability can promote cancer development and drug resistance, it can cause cancer cell death when genomic instability continues to increase to a limiting level; thus, genomic instability has therapeutic potential for treating cancer (5)(6)(7), and elucidating the specific regulatory mechanisms involved is of great significance.…”

Section: Introductionmentioning

confidence: 99%

Long non‑coding RNAs interact with RNA‑binding proteins to regulate genomic instability in cancer cells (Review)

2022

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Genomic instability, a feature of most cancers, contributes to malignant cell transformation and cancer progression due to the accumulation of genetic alterations. Genomic instability is reflected at numerous levels, from single nucleotide to the chromosome levels. However, the exact molecular mechanisms and regulators of genomic instability in cancer remain unclear. Growing evidence indicates that the binding of long non-coding RNAs (lncRNAs) to protein chaperones confers a variety of regulatory functions, including managing of genomic instability. The aim of the present review was to examine the roles of mitosis, telomeres, DNA repair, and epigenetics in genomic instability, and the mechanisms by which lncRNAs regulate them by binding proteins in cancer cells. This review contributes to our understanding of the role of lncRNAs and genomic instability in cancer and can potentially provide entry points and molecular targets for cancer therapies. Contents1. Introduction 2. LncRNAs affect chromosome instability via RBPs 3. LncRNAs are involved in DNA repair through RBPs 4. LncRNAs regulate other epigenetic modalities through RBPs 5.

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Origin of Genome Instability and Determinants of Mutational Landscape in Cancer Cells

Cited by 10 publications

References 87 publications

HHV-6A Infection of Papillary Thyroid Cancer Cells Induces Several Effects Related to Cancer Progression

HHV-6A Infection of Papillary Thyroid Cancer Cells Induces Several Effects Related to Cancer Progression

DNA replication initiation factor RECQ4 possesses a role in antagonizing DNA replication initiation

Long non‑coding RNAs interact with RNA‑binding proteins to regulate genomic instability in cancer cells (Review)

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