1. Cancer‐associated POT1 mutations lead to telomere elongation without induction of a DNA damage response
- Author
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Joshua Z Johnson, Dirk Hockemeyer, Kelsey M. Hennick, Brendan Finnerty, Mary L McMaster, Ryan Forster, Casey Drubin, Sarah B. Short, Won-Tae Kim, and Seung-A Sara Choo
- Subjects
Genome instability ,Male ,DNA damage ,Nonsense mutation ,Telomere-Binding Proteins ,Biology ,medicine.disease_cause ,General Biochemistry, Genetics and Molecular Biology ,Article ,Shelterin Complex ,humanized mouse models ,03 medical and health sciences ,Mice ,0302 clinical medicine ,POT1 ,Neoplasms ,medicine ,cancer ,genome editing ,Animals ,Humans ,Molecular Biology ,030304 developmental biology ,0303 health sciences ,General Immunology and Microbiology ,General Neuroscience ,Melanoma ,Stem Cells ,Cancer ,DNA Replication, Repair & Recombination ,Articles ,Telomere ,Shelterin ,medicine.disease ,telomeres ,human stem cells ,Mutation ,Cancer research ,Female ,Carcinogenesis ,K562 Cells ,030217 neurology & neurosurgery ,DNA Damage - 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., Genome‐engineering in human cells demonstrates that mutations in human shelterin subunit POT1 do not confer a selective disadvantage, and may contribute to tumorigenesis via increased telomere length and proliferative capacity.
- Published
- 2021