Schematic representation of RTEL1 roles in telomere dysfunction. In normal conditions, RTEL1 promotes G4 quadruplex and t-loop unwinding for DNA replication. The RING-domain mutations inhibit RTEL1-TRF2 interaction and then t-loop resolution.5 Thus, abnormal SXL4/1 activation persistently cuts t-loops, leading to telomere shortening as well as the accumulation of t-circles in cells. Short telomeres, commonly seen in patients with mutated RTEL1, trigger cell senescence and apoptosis via p53, leading to hematopoietic stem cell depletion in BM. However, some RTEL1 mutations were related to excessive 3′ overhang attrition in the absence of telomere shortening. In the context of cells maintaining their telomere lengths, the sustained DNA damage response activation caused by uncapped telomeres may promote leukemogenesis by molecular pathways distinct from typical accelerated telomere attrition associated with very short telomeres. Also, different RTEL1 variants modulated TRF2 expression in vitro, which may be an alternative mechanism related to RTEL1 dysfunction rather than impaired t-loop disassembly alone. DDR, DNA damage response; HSC, hematopoietic stem cell.
