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

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.

• Authors: Bernadette Nera, Hui-Shun Huang, Eric A Hendrickson, Lifeng Xu
• Journal: Cell cycle (Georgetown, Tex.) (Cell Cycle) Vol. 18 Issue 8 Pg. 880-888 (04 2019) ISSN: 1551-4005 [Electronic] United States
• PMID: 30907229 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• LIG4 protein, human
• Poly-ADP-Ribose Binding Proteins
• TERF2 protein, human
• Telomeric Repeat Binding Protein 2
• DNA Ligase ATP
• LIG3 protein, human

Topics

• Chromatids (metabolism)
• Colorectal Neoplasms (metabolism)
• DNA End-Joining Repair (genetics)
• DNA Ligase ATP (deficiency)
• Evolution, Molecular
• Genetic Vectors
• Genomic Instability (genetics)
• HCT116 Cells
• Humans
• Plasmids (genetics)
• Poly-ADP-Ribose Binding Proteins (deficiency)
• Sister Chromatid Exchange (genetics)
• Telomere (metabolism)
• Telomere Shortening (genetics)
• Telomeric Repeat Binding Protein 2 (genetics, metabolism)