LINE-1 expression in cancer correlates with p53 mutation, copy number alteration, and S phase checkpoint.
Wilson McKerrowXuya WangCarlos Mendez-DorantesPaolo MitaSong CaoMark GrivainisLi DingJohn LaCavaKathleen H BurnsJef D BoekeDavid FenyöPublished in: Proceedings of the National Academy of Sciences of the United States of America (2022)
Retrotransposons are genomic DNA sequences that copy themselves to new genomic locations via RNA intermediates; LINE-1 is the only active and autonomous retrotransposon in the human genome. The mobility of LINE-1 is largely repressed in somatic tissues but is derepressed in many cancers, where LINE-1 retrotransposition is correlated with p53 mutation and copy number alteration (CNA). In cell lines, inducing LINE-1 expression can cause double-strand breaks (DSBs) and replication stress. Reanalyzing multiomic data from breast, ovarian, endometrial, and colon cancers, we confirmed correlations between LINE-1 expression, p53 mutation status, and CNA. We observed a consistent correlation between LINE-1 expression and the abundance of DNA replication complex components, indicating that LINE-1 may also induce replication stress in human tumors. In endometrial cancer, high-quality phosphoproteomic data allowed us to identify the DSB-induced ATM-MRN-SMC S phase checkpoint pathway as the primary DNA damage response (DDR) pathway associated with LINE-1 expression. Induction of LINE-1 expression in an in vitro model led to increased phosphorylation of MRN complex member RAD50, suggesting that LINE-1 directly activates this pathway.
Keyphrases
- copy number
- poor prognosis
- mitochondrial dna
- endometrial cancer
- dna damage
- endothelial cells
- binding protein
- genome wide
- dna damage response
- dna repair
- gene expression
- cell cycle
- machine learning
- cell proliferation
- high glucose
- circulating tumor
- microbial community
- drug induced
- diabetic rats
- cell free
- wastewater treatment