Model for the role of mutagenic TLS in maintenance of the hematopoietic system. (A) Genomic nucleotides, damaged by endogenous sources or by chemical decay, form a threat to DNA transactions such as transcription or replication, in case they remain unrepaired. (B) Processive replication is arrested by a nucleotide, damaged by a helix-distorting oxidative nucleotide lesion. (C) The damaged nucleotide is bypassed by TLS. This prevents replication stress, but at the expense of the frequent incorporation of an incorrect nucleotide opposite the lesion (in red). (D) Subsequent repair of the damaged nucleotide, or replication of the bottom DNA strand, fixates the mutation. This contributes to the acquisition of clonal mutations in the aging hematopoietic system. Mutations in hematopoietic cells acquired during aging have been associated with the development of myeloid neoplasms in humans. (E) Stalled replicons that are not released by TLS can collapse to dsDNA breaks. DNA damage signaling at ssDNA gaps opposing the lesions and at dsDNA breaks induces senescence or apoptosis, ultimately resulting in collapse of the hematopoietic system. (F) We hypothesize that failure to release arrested replicons may underlie the observed mitochondrial dysfunction, possibly via depletion of NAD⁺ that is required simultaneously at DNA breaks and for mitochondrial respiration. This may lead to increased ROS production and to the induction of additional oxidative DNA lesions. A positive feedback loop between replication stress at the nuclear genome and mitochondrial dysfunction is proposed to further accelerate the collapse of the hematopoietic system.