ReviewTransposons: Unexpected players in cancer
Introduction
Transposons or transposable elements (TEs) are repetitive mobile genomic sequences having the ability to integrate into new sites in the genome. After discovery as jumping genes by Barbara McClintock (1950) various studies came up with the impact of TEs on genome structure, function and evolution. Transposons are prevalent in all organisms including plants and animals. They comprise 45% of the human genome (Cordaux and Batzer, 2009, Lander et al., 2001). Based on the mechanism of jumping, called transposition, they can be broadly divided into two major classes: DNA transposons and retrotransposons. DNA transposons move through a DNA intermediate mostly by “cut-and-paste” mechanism. Retrotransposons, also called retroelements, move through an RNA intermediate using the “copy-and-paste” mechanism. Retrotransposons are subdivided into long terminal repeat (LTR) and non-LTR retrotransposons based on the presence or absence of LTRs. No activity of DNA transposons was observed in the human genome for the last 50 million years (Lander et al., 2001). In humans, LTR retrotransposons include human endogenous retrovirus (HERVs) and non-LTR retrotransposons include long interspersed nuclear elements (LINEs), short interspersed nuclear elements (SINEs), and SINE-VNTR-Alu elements (SVAs) (Mills et al., 2007). SINEs and SVAs are non-autonomous transposons due to a lack of transposase enzyme, which is essential for transposition. Hence, they rely on autonomous transposons such as LINEs (Dewannieux et al., 2003). In humans, L1 (LINE) and Alu (SINE) elements are more abundant. Due to the smaller size of Alu elements, they are more abundant in copy number than LINEs. L1 elements represent 17–20% of human genome whereas Alu elements comprise about 11% of the human genome (Cordaux and Batzer, 2009, Lander et al., 2001). In contrast, HERVs constitute only 1% and SVAs constitute 0.2% of the human genome (Cordaux and Batzer, 2009, Wang et al., 2005).
Transposons play an active role in the regulation of gene expression. They have both positive and negative consequences on the genome. They maintain genome diversity leading to adaptive evolution (Schrader and Schmitz, 2019). They stabilize the genome by promoting heterochromatinization (Labrador and Corces, 2002) and their activation is crucial in different developmental stages in humans (Percharde et al., 2020). Despite their imperative role, they are generally silenced because of their deleterious effects on the genome (Morales et al., 2015). There are various mechanisms of methylation and chromatin remodeling of the genome to regulate these mobile elements (Castañeda et al., 2011, Yu et al., 2017).
A tight regulatory mechanism decides the expression pattern of TE throughout life starting from early embryogenesis (Deniz et al., 2019). Alteration in the regulatory mechanism can potentially create genomic instability, chromosomal breakage, and oncogenic activation, which consequently drives various autoimmune, neurological, and genetic disorders and is also reported in human cancer initiation and progression (Burns, 2020, Payer and Burns, 2019, Saleh et al., 2019). A number of risk factors such as environmental stress, aging and lifestyle influence the epigenetic patterns (Sen et al., 2016). For a better understanding of the role of these mobile elements in human cancer, this review focuses on key regulatory pathways of TEs and the impact of transposons on the genome during tumorigenesis and metastasis. Furthermore, how TEs play part in the three prevalent and deadliest cancer types for instance lung cancer, breast cancer and colorectal cancer is highlighted.
Section snippets
Multifarious roles of transposons
TEs are primers for adaptive evolution mediated by their ability to generate gene diversity. Adaptation to changes in environmental conditions is driven by positive selection due to genomic diversification involving recombination events involving TEs. Natural selection eliminates deleterious TE insertions affecting the fitness of the host (Piacentini et al., 2014). TEs persist in the genome through transposition within the genome, vertical transmission to progeny and horizontal transfer between
Silencing of transposons
During development, humans undergo two major epigenetic reprogramming: first during pre-implantation and second during gametogenesis. DNA hypomethylation often coincides with the upregulation of transposons in mammals (Molaro et al., 2014). Several regulatory elements interact to regulate the activity of these mobile elements in embryonic, germline and somatic cells.
Krüppel associated box-containing zinc finger proteins (KRAB-ZFPs) are the controller of mammalian TE regulation in embryonic as
Early embryogenesis
During early embryonic development a DNA demethylase, ten-eleven translocation (TET) enzyme, plays a role in demethylation at CpG sites and oxidation of 5-methyl Cytosine (5mC) at LINE-1, SINEs and DNA transposons in a replication-independent pathway (Ficz et al., 2011). The oxidized products of 5mC help in the downstream process by recruiting modification specific readers and preventing binding of some transcription factors (Gu et al., 2011). The enzyme also recruits co-activators such as
Gene expression alteration by insertion
Active TEs are capable of randomly inserting at any site in the genome. Insertion in the exonic regions of any gene can directly disrupt the function of the gene (Fig. 1A) that could lead to several genetic diseases and cancer (Kaer and Speek, 2013, Lee et al., 2012). Transposons entrapping gene fragments can insert new exons which can alter gene function (Fig. 1B) (Krasileva, 2019). The introduction of regulatory motifs in promoter and enhancer regions could increase or decrease gene
Transposons in lung cancer
Lung cancer is the most diagnosed cancer with the highest death incidence. International Agency for Research on Cancer estimated lung cancer as a reason for 18% of all cancer deaths in 2020 (Sung et al., 2021). In India, lung cancer accounts for 11.3% of new cancers and 13.7% of cancer deaths (Behera, 2017). The risk factors comprise smoking and environmental pollution (de Groot et al., 2018). Transposons taking part in genomic instability could be a major risk factor in lung carcinogenesis.
Transposons in breast cancer
Breast cancer is the most common type of cancer in women and the second most prevalent cancer after lung cancer. Global cancer statistics recorded 2.3 million new cases of breast cancer in 2020 which exceed that of lung cancer (Sung et al., 2021). Risk factors associated with breast cancer include age, lifestyle (physical activity, diet, cigarette smoking, alcohol drinking) and environmental exposures (persistent organic pollutants, air pollution, lead, arsenic) (Lee and Pausova, 2013, Terry et
Transposons in colorectal cancer
Colorectal cancer (CRC) is the third most frequent cancer worldwide after lung cancer and breast cancer. GLOBOCAN 2020 estimated 9.4% of cancer deaths by CRCs making it the second most deadly cancer after lung cancer (Sung et al., 2021). It is the second most common type of cancer in females after breast cancer (Mármol et al., 2017). The incidence of CRCs shows a direct relationship with smoking habit, anthropometry, age and lifestyle of a person, and environmental exposure (Murphy et al., 2019
Future perspectives
The protein coding genes are the major source of genomic biomarkers in cancer to date, although they comprise only about 1.5% of the genome (Consortium, 2007). Expression patterns of lncRNAs and microRNAs have been proposed as signature markers in many cancer types (Anfossi et al., 2018, Chandra Gupta and Nandan Tripathi, 2017, Slack and Chinnaiyan, 2019). Besides the fact that these non-coding RNAs are derived from repetitive sequences and a majority of the repetitive genome is transposon
Conclusion
Transposons are repetitive DNA sequences and constitute a large portion of the human genome. Their role in adaptive evolution, structural and functional regulation of gene expression provides insights into complex mechanisms of genome stability and diversity maintenance. A causal relationship between transposon dysregulation and carcinogenesis and its application in cancer prognosis, diagnosis and treatment is often overlooked. Our current understanding on transposons is just the tip of the
Declaration of Competing Interest
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
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