Cancer-associated POT1 mutations lead to telomere elongation without induction of a DNA damage response.

Abstract

Mutations in the shelterin protein POT1 are associated with chronic lymphocytic leukemia (CLL), Hodgkin lymphoma, angiosarcoma, melanoma, and other cancers. These cancer-associated POT1 (caPOT1) mutations are generally heterozygous, missense, or nonsense mutations occurring throughout the POT1 reading frame. Cancers with caPOT1 mutations have elongated telomeres and show increased genomic instability, but which of the two phenotypes promotes tumorigenesis is unclear. We tested the effects of CAS9-engineered caPOT1 mutations in human embryonic and hematopoietic stem cells (hESCs and HSCs, respectively). HSCs with caPOT1 mutations did not show overt telomere damage. In vitro and in vivo competition experiments showed the caPOT1 mutations did not confer a selective disadvantage. Since DNA damage signaling is known to affect the fitness of HSCs, the data argue that caPOT1 mutations do not cause significant telomere damage. Furthermore, hESC lines with caPOT1 mutations showed no detectable telomere damage response while showing consistent telomere elongation. Thus, caPOT1 mutations are likely selected for during cancer progression because of their ability to elongate telomeres and extend the proliferative capacity of the incipient cancer cells.

• Authors: Won-Tae Kim, Kelsey Hennick, Joshua Johnson, Brendan Finnerty, Seunga Choo, Sarah B Short, Casey Drubin, Ryan Forster, Mary L McMaster, Dirk Hockemeyer
• Journal: The EMBO journal (EMBO J) Vol. 40 Issue 12 Pg. e107346 (06 15 2021) ISSN: 1460-2075 [Electronic] England
• PMID: 33934394 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, N.I.H., Intramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)
• Copyright: © 2021 The Authors. Published under the terms of the CC BY NC ND 4.0 license.

Chemical References

• POT1 protein, human
• Shelterin Complex
• Telomere-Binding Proteins

Topics

• Animals
• DNA Damage
• Female
• Humans
• K562 Cells
• Male
• Mice
• Mutation
• Neoplasms (genetics)
• Shelterin Complex
• Stem Cells
• Telomere
• Telomere-Binding Proteins (genetics)