Biology subjects

Smoom, R.

Publications and source records attributed to Smoom, R..

3 recordsLinked to original sources

bioRxiv2025

Human length telomeres restrict the regenerative potential of hematopoietic stem cells in mice

Extremely short telomeres cause bone marrow failure in telomere biology disorder (TBDs) patients. Here, we employed the recently developed Telomouse with human-length telomeres resulting from a single amino acid substitution in the helicase Rtel1 (Rtel1M492K/M492K) to determine the effects of the short telomeres on the bone marrow and hematopoiesis. Under homeostatic conditions, Telomice have notably short telomeres but normal hematopoiesis. However, when forced to repopulate following repeated treatment with 5-fluoro-uracil or upon bone marrow transplantation into lethally irradiated mice, bone marrow progenitor cells are significantly depleted in Telomice compared to wild-type controls. This effect is associated with increased frequency of telomere repeat arrays too short to be detected by fluorescence in situ hybridization in the bone marrow of Telomice.

genetics↗

bioRxiv2024

Separation of telomere protection from length regulation by two different point mutations at amino acid 492 of RTEL1

RTEL1 is an essential DNA helicase that plays multiple roles in genome stability and telomere length regulation. A variant of RTEL1 with a lysine at position 492 is associated with short telomeres in Mus spretus, while a conserved methionine at this position is found in M. musculus, which has ultra-long telomeres. In humans, a missense mutation at this position (Rtel1M492I) causes a fatal telomere biology disease termed Hoyeraal-Hreidarsson syndrome (HHS). Introducing the Rtel1M492K mutation into M. musculus shortened the telomeres of the resulting strain, termed Telomouse, to the length of human telomeres. Here, we report on a mouse strain carrying the Rtel1M492I mutation, termed HHS mouse. The HHS mouse telomeres are not as short as those of Telomice but nevertheless they display higher levels of telomeric DNA damage, fragility and recombination, associated with anaphase bridges and micronuclei. These observations indicate that the two mutations separate critical functions of RTEL1: M492K mainly reduces the telomere length setpoint, while M492I predominantly disrupts telomere protection. The two mouse models enable dissecting the mechanistic roles of RTEL1 and the different contributions of short telomeres and DNA damage to telomere biology diseases, genomic instability, cancer, and aging.

genetics↗

bioRxiv2021

A single amino acid in RTEL1 determines telomere length in mice

Telomeres, the ends of eukaryotic chromosomes, protect genome integrity and enable cell proliferation. Maintaining optimal telomere length in the germline and throughout life limits the risk of cancer and enables healthy aging. Telomeres in the house mouse, Mus musculus, are about five times longer than human telomeres, limiting the use of this common laboratory animal for studying the contribution of telomere biology to aging and cancer. We identified a key amino acid variation in the helicase RTEL1, naturally occurring in the short-telomere mouse species M. spretus. Introducing this variation into M. musculus is sufficient to reduce the telomere length set point in the germline and generate mice with human-length telomeres. While these mice are fertile and appear healthy, the regenerative capacity of their colonic epithelium is compromised. The engineered Telomouse reported here demonstrates a dominant role of RTEL1 in telomere length regulation and provides a unique model for aging and cancer.

genetics↗