Cancer‐associated POT1 mutations lead to telomere elongation without induction of a DNA damage response. (2nd May 2021)

• Record Type: Journal Article
• Authors: Kim, Won‐Tae; Hennick, Kelsey; Johnson, Joshua; Finnerty, Brendan; Choo, Seunga; Short, Sarah B; Drubin, Casey; Forster, Ryan; McMaster, Mary L; Hockemeyer, Dirk
• Is Part Of: EMBO journal. Volume 40:Number 12(2021)
• Page Start: n/a
• Page End: n/a
• Publication Date: 2021-05-02
• Subjects: cancer -- genome editing -- human stem cells -- humanized mouse models -- POT1 -- telomeres; Molecular biology -- Periodicals; 572.805
• DOI: 10.15252/embj.2020107346
• Languages: English
• ISSNs: 0261-4189

Abstract

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. SYNOPSIS: Whether cancer‐associated mutations in human shelterin protein POT1 (caPOT1) contribute to tumorigenesis via the connected phenomena of telomere elongation or genomic instability has remained controversial. Here, genome editing in human cells demonstrates that caPOT1 mutations lead to telomere elongation without triggering telomeric DNA damage responses. Engineered caPOT1 mutations do not induce DNA damage responses at telomeres but leads to telomere elongation in hESCs. caPOT1 mutations do not confer strong proliferative disadvantages in hematopoietic stem cells and differentiated cells in vitro . caPOT1 mutations are not selected against within the population in a humanized mouse model in vivo . The familial caPOT1 Y36H mutation leads to telomere elongation in somatic tissues. Abstract : 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.