The review summarizes literature data on the role of DNA breaks and DNA repair in differentiation of pluripotent stem cells (PSC) and connective cell lineages. PSC, including embryonic stem cells (ESC) and induced pluripotent stem cells (iPSC), are rapidly dividing cells with highly active DNA damage response (DDR) mechanisms to ensure the stability and integrity of the DNA. In PSCs, the most common DDR mechanism is error-free homologous recombination (HR) that is primarily active during S phase of the cell cycle, whereas in quiescent, slow-dividing or non-dividing tissue progenitors and terminally differentiated cells, error-prone non-homologous end joining (NHEJ) mechanism of the double-strand break (DSB) repair is dominating. Thus, it seems that reprogramming and differentiation induce DNA strand breaks in stem cells which itself may trigger the differentiation process. Somatic cell reprogramming to iPSCs is preceded by a transient increase of the DSBs induced presumably by the caspase-dependent DNase or reactive oxygen species (ROS). In general, pluripotent stem cells possess stronger DNA repair systems compared to the differentiated cells. Nonetheless, during a prolonged cell culture propagation, DNA breaks can accumulate due to the DNA polymerase stalling. Consequently, the DNA damage might trigger the differentiation of stem cells or a replicative senescence of somatic cells. Differentiation process per se is often accompanied by a decrease of the DNA repair capacity. Thus, the differentiation might be triggered by DNA breaks, alternatively the breaks can be a consequence of the decay in the DNA repair capacity of differentiated cells.

该综述总结了有关 DNA 断裂和 DNA 修复在多能干细胞 (PSC) 和结缔细胞谱系分化中的作用的文献数据。PSC 包括胚胎干细胞 (ESC) 和诱导多能干细胞 (iPSC)，它们是快速分裂的细胞，具有高度活跃的 DNA 损伤反应 (DDR) 机制，可确保 DNA 的稳定性和完整性。在 PSC 中，最常见的 DDR 机制是无错误同源重组 (HR)，主要在细胞周期的 S 期活跃，而在静止、缓慢分裂或非分裂的组织祖细胞和终末分化细胞中，容易出错双链断裂（DSB）修复的非同源末端连接（NHEJ）机制占主导地位。因此，似乎重编程和分化会诱导干细胞中的 DNA 链断裂，这本身可能会触发分化过程。在体细胞重编程为 iPSC 之前，DSB 的瞬时增加可能是由半胱天冬酶依赖性 DNase 或活性氧 (ROS) 诱导的。一般来说，与分化细胞相比，多能干细胞具有更强的 DNA 修复系统。尽管如此，在延长的细胞培养繁殖过程中，由于 DNA 聚合酶停滞，DNA 断裂会累积。因此，DNA 损伤可能会触发干细胞的分化或体细胞的复制衰老。分化过程 在体细胞重编程为 iPSC 之前，DSB 的瞬时增加可能是由半胱天冬酶依赖性 DNase 或活性氧 (ROS) 诱导的。一般来说，与分化细胞相比，多能干细胞具有更强的 DNA 修复系统。尽管如此，在延长的细胞培养繁殖过程中，由于 DNA 聚合酶停滞，DNA 断裂会累积。因此，DNA 损伤可能会触发干细胞的分化或体细胞的复制衰老。分化过程 在体细胞重编程为 iPSC 之前，DSB 的瞬时增加可能是由半胱天冬酶依赖性 DNase 或活性氧 (ROS) 诱导的。一般来说，与分化细胞相比，多能干细胞具有更强的 DNA 修复系统。尽管如此，在延长的细胞培养繁殖过程中，由于 DNA 聚合酶停滞，DNA 断裂会累积。因此，DNA 损伤可能会触发干细胞的分化或体细胞的复制衰老。分化过程 DNA 损伤可能会触发干细胞的分化或体细胞的复制衰老。分化过程 DNA 损伤可能会触发干细胞的分化或体细胞的复制衰老。分化过程本身往往伴随着 DNA 修复能力的下降。因此，分化可能是由 DNA 断裂引发的，或者断裂可能是分化细胞 DNA 修复能力衰退的结果。