MULTI-ORGAN FAILURE DRIVEN BY TELOMERE UNCAPPING

The telomere-bound shelterin complex safeguards chromosome ends from being recognized as DNA double-strand breaks, a function mostly dependent on TRF2. Loss of TRF2 results in telomere uncapping, activation of the DNA damage response, and chromosomal end-to-end fusions, with dramatic consequences for genome integrity and cell fate. The impact of TRF2 depletion is context-dependent, causing distinct outcomes in different cell types, however the systemic effects of acute TRF2 loss have remained poorly characterized. In this work, we adopted an inducible Trf2 knockout mouse model to investigate the consequences of telomere uncapping at the organismal level. Trf2 deletion was rapidly achieved across multiple tissues and this event was accompanied by DDR activation and multi-organ functional failure, ultimately leading to lethality within approximately one week. Trf2 knockout elicited a syndrome resembling that occurring upon exposure to high doses of ionizing radiation, including severe bone marrow hypoplasia, leukopenia, hematopoietic stem and progenitor cell dysfunction, and intestinal epithelium degeneration. Bone marrow transplantation failed to extend lifespan in Trf2 knockout mice, whereas it rescued the mortality caused by X-rays at low doses, highlighting the fact that lethality is not primarily dictated by the hematopoietic system, but the consequences of TRF2 loss extend to other organs. Our study demonstrates the essential role of TRF2 in preserving the integrity of the hematopoietic and intestinal systems, presumably owing to their highly proliferative nature, and underscores the catastrophic outcomes of its loss at the organismal level, aligning the effects of telomere uncapping with the pathophysiology of acute radiation syndrome.