Both the classical and alternative non-homologous end joining pathways contribute to the fusion of drastically shortened telomeres induced by TRF2 overexpression

Bernadette Nera, Hui Shun Huang, Eric A. Hendrickson, Lifeng Xu

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

Abstract

The double-stranded telomeric binding protein TRF2 is expressed in many human cancers at elevated levels. Moreover, experimental overexpression of TRF2 in human cells causes replication stalling in telomeric tracts, which leads to drastic telomere shortening and fusion of deprotected chromosome ends. To understand which end joining pathway is involved in mediating these chromosome fusions, we overexpressed TRF2 in human HCT116 cell lines that were deficient for the DNA Ligase 4 (Lig4)-dependent classical non-homologous end joining (C-NHEJ) or the DNA Ligase 3 (Lig3)-dependent alternative non-homologous end joining (A-NHEJ) pathway. Surprisingly, abrogation of either Lig4 or nuclear Lig3 significantly reduced inter-chromosomal fusion of drastically shortened telomeres, suggesting that both the C-NHEJ and A-NHEJ pathways are involved in mediating this type of fusion. Fusion between deprotected sister chromatids, however, only required the Lig3-dependent A-NHEJ pathway. Interestingly, a previous study reported similar end joining pathway requirements for the fusion of critically shortened telomeres during a telomere attrition-based cellular crisis. We speculate that, as in cellular crisis, the same repair pathway(s) may drive clonal and genomic evolution in human cancers containing elevated TRF2 levels.

Original languageEnglish (US)
Pages (from-to)880-888
Number of pages9
JournalCell Cycle
Volume18
Issue number8
DOIs
StatePublished - Apr 18 2019

Bibliographical note

Funding Information:
This work was funded by an American Cancer Society Research Scholar Grant RSG-12-069-01-DMC to L.X. Work in the Hendrickson laboratory was funded, in part, through grants from the National Institutes of Health (GM088351) and the National Cancer Institute (CA190492).

Publisher Copyright:
© 2019, © 2019 Informa UK Limited, trading as Taylor & Francis Group.

Keywords

  • Lig3-dependent A-NHEJ
  • Lig4-dependent C-NHEJ
  • TRF2 overexpression
  • drastic telomere shortening
  • inter-chromosomal fusions
  • sister chromatid fusions

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