All y'all need to know 'bout retroelements in cancer

Abstract

Genetic instability is one of the principal hallmarks and causative factors in cancer. Human transposable elements (TE) have been reported to cause human diseases, including several types of cancer through insertional mutagenesis of genes critical for preventing or driving malignant transformation. In addition to retrotransposition-associated mutagenesis, TEs have been found to contribute even more genomic rearrangements through non-allelic homologous recombination. TEs also have the potential to generate a wide range of mutations derivation of which is difficult to directly trace to mobile elements, including double strand breaks that may trigger mutagenic genomic rearrangements. Genome-wide hypomethylation of TE promoters and significantly elevated TE expression in almost all human cancers often accompanied by the loss of critical DNA sensing and repair pathways suggests that the negative impact of mobile elements on genome stability should increase as human tumors evolve. The biological consequences of elevated retroelement expression, such as the rate of their amplification, in human cancers remain obscure, particularly, how this increase translates into disease-relevant mutations. This review is focused on the cellular mechanisms that control human TE-associated mutagenesis in cancer and summarizes the current understanding of TE contribution to genetic instability in human malignancies.

Figure 1

A. Schematic of the genome organization of active human retroelements. LINE-1 consists of a 5′ UTR, an inter ORF region, and 3′UTR (light grey boxes) that ends in a polyadenylation signal (pA) and a run of adenosines (AAA). L1 encodes two open reading frames , ORF1 (green box) and ORF2. ORF2 encodes a protein with endonuclease (EN; yellow box) and reverse transcriptase (RT; red box) activities. The ~300 bp human SINE, Alu, is composed of two non-identical 7SL-derived monomers (light grey boxes) that are connected by an adenosine (A)-rich linker. The Alu element ends in a variable length stretch of adenosines (AAA). SVA elements consist of four distinct regions: CCCTCT repeats, an inverted Alu-like sequence, VNTR variable number of tandem repeats, and human endogenous retrovirus (HERV) -like sequence. The approximate length of each element is shown in parentheses. B. L1 integration steps and outcomes. TTAAAA is the consensus L1 endonuclease recognition site. A blue box represents a transcriptionally active and retrotranspositionally competent L1 locus in the human genome. The L1 RNP (ribonucleoprotein particle) is composed of the L1 mRNA (blue), L1 ORF1 protein (green) and L1 ORF2 protein that contains endonuclease (EN, yellow) and reverse transcriptase (RT, red) domains. The L1 RNP or L1 ORF2 recognizes an L1 target site in the human genome and generates a first DNA nick that at some point during retrotransposition becomes a DNA double strand break (DSB). The polyA tail of the L1 mRNA base pairs with the DNA at the nick that serves as a primer for TPRT (target primed reverse transcription) by L1 RT that generates a cDNA ‘flap’ (red). This intermediate can be resolved to generate de novo L1 integration event (green box), integration-associated genomic rearrangements, or it can be recognized and aborted by ERCC1/XPF complex, a component of the nucleotide excision repair machinery, leading to the restoration of the integration site.

Figure 2. Estimated contribution of various types of retroelement-induced mutagenesis to genomic instability

The three main types of L1-, Alu-, and SVA-related mutagenesis such as insertional , recombination, and error-prone DSB repair are represented. The relative contribution of L1, Alu, and SVA (with SVA set at 1) to insertional mutagenesis (shown in light blue, yellow, and purple, respectively) is estimated based on the reported disease incidence (reviewed in Belancio et.al., 2008). The relative contribution of L1 and Alu to recombination (shown in dark blue and green, respectively) is estimated based on disease and recombination-associated deletions (Deininger and Batzer, 1999, Han K. et.al., 2007, Han K. et.al., 2008). The potential relative mutagenic contribution of the L1-induced DSBs (shown in red) is essentially unknown and example estimates of 0.5 and 50 relative to insertion events are presented for comparison.

Figure 3. TE-derived changes in the cancer transcriptome

Gene expression can be affected by the presence of mobile element sequences near, or within, genes. The unmethylated status observed in cancer cells usually leads to the loss of transcriptional regulation of TE promoters affecting nearby genes as shown in A) where the antisense promoter (ASP) activity of a full-length L1 element (blue) can drive expression of genes immediately adjacent to these sequences (Nigumann et.al. 2002;Speek 2001) and B) by the expression of miRs from upstream pol III-containing Alu elements (Borchert et.al. 2006). C) TE-derived sequences upstream of genes can supply regulatory sequences such as p53 sites affecting gene expression (Zemojtel et al., 2009); or D) introduce splicing and polyadenylation signals changing transcriptional products leading to events such as exonization s that can alter protein function (Yi et al., 2003). E) The presence of repeated sequences in opposite orientation within transcripts can form double stranded RNA (dsRNA) which is modified by RNA editing enzymes with a potential impact on expression of the gene.

Figure 4. the “double-edge sword” hypothesis

Environmentally induced changes either due to transient exposures (e.g. demethylating agents) alone or in combination with genetic defects, such as DNA repair deficiencies in cancerous cells, can lead to a diminished regulation of mobile elements. The increase in activity and/or deregulated transcription of TE promoters can have an agonistic effect such as promoting apoptosis or alternatively have an antagonistic effect by inducing changes leading to chemotherapeutic resistance, proliferation or even the generation of secondary malignancies.