LINE-1 expression in cancer correlates with p53 mutation, copy number alteration, and S phase checkpoint

Wilson McKerrow, Xuya Wang, Carlos Mendez-Dorantes, Paolo Mita, Song Cao, Mark Grivainis, Li Ding, John LaCava, Kathleen H. Burns, Jef D. Boeke, David Fenyö

Research output: Contribution to journalArticlepeer-review

4 Scopus citations

Abstract

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.

Original languageEnglish
Article numbere2115999119
JournalProceedings of the National Academy of Sciences of the United States of America
Volume119
Issue number8
DOIs
StatePublished - Feb 22 2022

Keywords

  • Cancer
  • Copy number alteration
  • DNA damage response
  • LINE-1
  • Retrotransposon

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