LINE-1 expression in cancer correlates with DNA damage response, copy number variation, and cell cycle progression

Abstract

Retrotransposons are genomic DNA sequences that are capable of copying themselves to new genomic locations via RNA intermediates; LINE-1 is the only retrotransposon that remains autonomous and active in the human genome. The mobility of LINE-1 is largely repressed in somatic tissues, but LINE-1 is active in many cancers. Recent studies using LINE-1 constructs indicate that host cells activate a DNA damage response (DDR) to repair retrotransposition intermediates and resolve conflicts between LINE-1 and DNA replication. Using multi-omic data from the CPTAC project, we found correlations between LINE-1 expression and ATM-MRN-SMC DDR signalling in endometrial cancer and between LINE-1 and the ATR-CHEK1 pathway in p53 wild type breast cancer. This provides evidence that conflicts between LINE-1 and DNA replication occur in at least some human cancers. Furthermore, LINE-1 expression in these cancers is correlated with the total amount of copy number variation genome wide, indicating that, when active in cancer, pointing to a direct impact of LINE-1 associated DNA damage on genome structure. We also find that, in endometrial and ovarian cancer, LINE-1 expression is correlated with the expression of genes that drive cycle progression including E2F3, PLK1 and Aurora kinase B. This study provides evidence, supporting recent work in model cell lines, of a LINE-1/DDR connection in human tumors and raises the possibility of additional interactions between LINE-1 and the cell cycle.

LINE-1 Retrotransposon expression in cancerous, epithelial and neuronal cells revealed by 5’ single-cell RNA-Seq

“…However, we also saw a high level of inferred "LINE-1" expression across all cell types (figure 1B). This is an unreasonable result given that previous IHC experiments show that LINE-1 is specifically overexpressed in cancer cells 2 , and our own analyses of tumor transcriptomes and proteomes indicate that LINE-1 expression is highly enriched in tumors compared to adjacent normal tissue 13 . Thus, we concluded that, in this analysis, any signal from LINE-1 has been almost completely overwhelmed by the presence of other transcripts that terminate at or near the 3' end of LINE-1.…”

“…While very strong evidence from both RNA and protein 36,46,47 shows that LINE-1 is highly expressed in many tumors, the extent of its expression in normal cellular contexts is much less well understood. New evidence has linked retrotransposons broadly or LINE-1 specifically to a variety of non-cancer diseases, including age-related inflammation 16,32 , neurodegenerative diseases 48–50 and autoimmune disorders 51,52 .…”

LINE-1 ORF1p RIP-seq reveals widespread association with p-body enriched mRNAs

“…However, mechanisms that limit LINE-1 expression are often dysfunctional in cancers, allowing for the expression and mobilization of LINE-1 [28,33,34]. LINE-1 expression has the potential to disrupt genomic stability, making it a likely component in cancer progression [35,36]. LINE-1 ORF1p expression has been observed in around 47% of tumors tested, and roughly in 40% of prostate tumors [33].…”