Crossing the LINE Toward Genomic Instability: LINE-1 Retrotransposition in Cancer

Kemp, Jacqueline; Longworth, Michelle S.

doi:10.3389/fchem.2015.00068

Cited by 72 publications

(64 citation statements)

References 113 publications

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“…In male mice, the extended lifespan linked to SIRT6 overexpression relates to a decrease in serum insulin-like growth factor (IGF-1) and increase in IGF-binding protein 1 (83). SIRT6 prevents genomic instability and aging-related cellular dysfunction by maintaining heterochromatin at long interspersed element-1 (LINE-1) retroelements, suppressing their transcription, and preventing retrotransposition events destabilizing the genome (89). Indeed, the SIRT6-dependent heterochromatin packaging of heterochromatin at LINE-1 retroelements suppresses the transposition, a function that can be compromised during aging (181).…”

Section: Sirt6 In Aging-related Endothelial Dysfunctionmentioning

confidence: 99%

SIRT1 and SIRT6 Signaling Pathways in Cardiovascular Disease Protection

D’Onofrio¹,

Servillo²,

Balestrieri³

2018

Antioxidants & Redox Signaling

285

238

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Significance: Oxidative stress represents the common hallmark of pathological conditions associated with cardiovascular disease (CVD), including atherosclerosis, heart failure, hypertension, aging, diabetes, and other vascular system-related diseases. The sirtuin (SIRT) family, comprising seven proteins (SIRT1-SIRT7) sharing a highly conserved nicotinamide adenine dinucleotide (NAD + )-binding catalytic domain, attracted a great attention for the past few years as stress adaptor and epigenetic enzymes involved in the cellular events controlling aging-related disorder, cancer, and CVD. Recent Advances: Among sirtuins, SIRT1 and SIRT6 are the best characterized for their protective roles against inflammation, vascular aging, heart disease, and atherosclerotic plaque development. This latest role has been only recently unveiled for SIRT6. Of interest, in recent years, complex signaling networks controlled by SIRT1 and SIRT6 common to stress resistance, vascular aging, and CVD have emerged. Critical Issues: We provide a comprehensive overview of recent developments on the molecular signaling pathways controlled by SIRT1 and SIRT6, two post-translational modifiers proven to be valuable tools to dampen inflammation and oxidative stress at the cardiovascular level. Future Directions: A deeper understanding of the epigenetic mechanisms through which SIRT1 and SIRT6 act in the signalings responsible for onset and development CVD is a prime scientific endeavor of the upcoming years. Multiple ''omic'' technologies will have widespread implications in understanding such mechanisms, speeding up the achievement of selective and efficient pharmacological modulation of sirtuins for future applications in the prevention and treatment of CVD. Antioxid. Redox Signal. 28, 711-732.

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Section: Sirt6 In Aging-related Endothelial Dysfunctionmentioning

confidence: 99%

SIRT1 and SIRT6 Signaling Pathways in Cardiovascular Disease Protection

D’Onofrio¹,

Servillo²,

Balestrieri³

2018

Antioxidants & Redox Signaling

285

238

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“…Retrotransposable elements (RTEs), especially Long Interspersed Element-1 (LINE-1) RTEs, comprise a significant fraction of mammalian genomes, and their transposition can give rise to genomic instability, mutagenesis, and transcriptional de-regulation [30]. Accumulating evidence suggests that heterochromatic silencing of such elements is compromised in aging cells and tissues [26].…”

Section: Heterochromatin Silencing and Genome Maintenance In Aging Anmentioning

confidence: 99%

SIRT6: Novel Mechanisms and Links to Aging and Disease

Tasselli

Zheng

Chua

2017

Trends in Endocrinology & Metabolism

220

201

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SIRT6, a member of the Sirtuin family of NAD+-dependent enzymes, has established roles in chromatin signaling and genome maintenance. Through these functions, SIRT6 protects against aging-associated pathologies including metabolic disease and cancer, and can promote longevity in mice. Research from the last few years has revealed that SIRT6 is a complex enzyme with multiple substrates and catalytic activities, and uncovered novel SIRT6 functions in maintenance of organismal health span. Here, we review these new discoveries and models of SIRT6 biology in four areas: heterochromatin stabilization and silencing, stem cell biology, cancer initiation and progression, and regulation of metabolic homeostasis. We discuss possible implications of these findings for therapeutic interventions in aging and aging-related disease processes.

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“…L1 insertions in particular have been implicated as potential cancer causing mutations in those and other studies (Morse et al, 1988; Miki et al, 1992; Iskow et al, 2010; Lee et al, 2012; Scott et al, 2016). L1 activity is thought to promote tumor development by causing genomic instability, via impaired chromosomal pairing during mitosis, and/or by disrupting coding or regulatory sequences (Kemp and Longworth, 2015). …”

Section: Introductionmentioning

confidence: 99%

Patterns of Transposable Element Expression and Insertion in Cancer

Clayton

Wang

Rishishwar

et al. 2016

Front. Mol. Biosci.

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Human transposable element (TE) activity in somatic tissues causes mutations that can contribute to tumorigenesis. Indeed, TE insertion mutations have been implicated in the etiology of a number of different cancer types. Nevertheless, the full extent of somatic TE activity, along with its relationship to tumorigenesis, have yet to be fully explored. Recent developments in bioinformatics software make it possible to analyze TE expression levels and TE insertional activity directly from transcriptome (RNA-seq) and whole genome (DNA-seq) next-generation sequence data. We applied these new sequence analysis techniques to matched normal and primary tumor patient samples from the Cancer Genome Atlas (TCGA) in order to analyze the patterns of TE expression and insertion for three cancer types: breast invasive carcinoma, head and neck squamous cell carcinoma, and lung adenocarcinoma. Our analysis focused on the three most abundant families of active human TEs: Alu, SVA, and L1. We found evidence for high levels of somatic TE activity for these three families in normal and cancer samples across diverse tissue types. Abundant transcripts for all three TE families were detected in both normal and cancer tissues along with an average of ~80 unique TE insertions per individual patient/tissue. We observed an increase in L1 transcript expression and L1 insertional activity in primary tumor samples for all three cancer types. Tumor-specific TE insertions are enriched for private mutations, consistent with a potentially causal role in tumorigenesis. We used genome feature analysis to investigate two specific cases of putative cancer-causing TE mutations in further detail. An Alu insertion in an upstream enhancer of the CBL tumor suppressor gene is associated with down-regulation of the gene in a single breast cancer patient, and an L1 insertion in the first exon of the BAALC gene also disrupts its expression in head and neck squamous cell carcinoma. Our results are consistent with widespread somatic activity of human TEs leading to numerous insertion mutations that can contribute to tumorigenesis in a variety of tissues.

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Crossing the LINE Toward Genomic Instability: LINE-1 Retrotransposition in Cancer

Cited by 72 publications

References 113 publications

SIRT1 and SIRT6 Signaling Pathways in Cardiovascular Disease Protection

SIRT1 and SIRT6 Signaling Pathways in Cardiovascular Disease Protection

SIRT6: Novel Mechanisms and Links to Aging and Disease

Patterns of Transposable Element Expression and Insertion in Cancer

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