Abstract
While the shelterin complex guards and coordinates the mechanism of telomere regulation, deregulation of this process is tightly linked to malignant transformation and cancer. Here, we present the novel finding of a germline stop-gain variant (p.Q199*) in the shelterin complex gene POT1, which was identified in a child with acute myeloid leukemia. We show that the cells overexpressing the mutated POT1 display increased DNA damage and chromosomal instabilities compared to the wildtype counterpart. Protein and mRNA expression analyses in the primary patient cells further confirm that, physiologically, the variant leads to a nonfunctional POT1 allele in the patient. Subsequent telomere length measurements in the primary cells carrying heterozygous POT1 p.Q199* as well as POT1 knockdown AML cells revealed telomeric elongation as the main functional effect. These results show a connection between POT1 p.Q199* and telomeric dysregulation and highlight POT1 germline deficiency as a predisposition to myeloid malignancies in childhood.
Highlights
Telomeres play an essential role in preserving our genetic material by protecting Telomeres play an essential role in preserving our genetic material by protecting chromosomal ends from degradation, while at the same time avoiding unwanted DNA chromosomal ends from degradation, while at the same time avoiding unwanted DNA damage responses [1]
To elucidate whether shelterin complex mutations can predispose to the development of pediatric cancer, we analysed whole exome sequencing data of two independent parent
23 variants were identified in 269 pediatric cancer patients (Figure 1B) across various tumor entities (Figure 1C), with missense mutations being the most prominent
Summary
Telomeres play an essential role in preserving our genetic material by protecting Telomeres play an essential role in preserving our genetic material by protecting chromosomal ends from degradation, while at the same time avoiding unwanted DNA chromosomal ends from degradation, while at the same time avoiding unwanted DNA damage responses [1]. The shelterin complex, which consists of six different protein damage responses [1]. The shelterin complex, which consists of six different protein subsubunits—TRF1, TRF2, RAP1, TIN2, TPP1 and POT1 (Figure 1A)—is responsible for units—TRF1, TRF2, RAP1, TIN2, TPP1 and POT1 (Figure 1A)—is responsible for safesafeguarding and properly maintaining telomeric DNA [2]. Shelterin deregulation leads guarding and properly maintaining telomeric DNA [2]. Shelterin deregulation leads to to uncapped telomeres, which subsequently risks irreversible cellular changes, including uncapped telomeres, which subsequently risks irreversible cellular changes, including gegenome instabilities, cellular aging or senescence and malignant transformation [3]. Nome instabilities, cellular aging or senescence and malignant transformation [3].
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