Even stored carefully and properly inside the cell nuclei, DNA is constantly attacked by endogenous and exogenous agents, causing surprisingly extensive DNA damage. The organisms have evolved DNA repair systems to cope with those potentially deleterious lesions [1]. The human nervous system is formed through the extensive proliferation of the neural stem cells that gradually exit from the cell cycle, migrate, and finally become longest-living “postmitotic” neurons at their destinations [2]. The DNA repair mechanism relying on homologous genetic recombination, which is operated during the S/G2 phase of the cell cycle, might be absent in the postmitotic cells, such as neurons [3]. At the same time, taking into consideration that the brain is thought to metabolize as much as a fifth of consumed oxygen, base lesions in the DNA generated by the attack from reactive oxygen species (ROS) over time are particularly serious for long-living neurons. Those are generally repaired by the base excision repair (BER) pathway [3]. ROS may also lead to form DNA single-strand breaks (SSBs) and double-strand breaks (DSBs), but SSBs might be crucial for postmitotic neurons [4]. These repair types of machinery are essential in the nervous system as the defect in the DNA repair system results in neurodegenerative disease or neurodevelopmental abnormality [3, 5]. However, the identity of DNA damages accrue and their distribution throughout the genome of postmitotic neurons remained elusive. Two studies independently appeared in the recent issues of Science [6], and Nature [7] now delineate the identity of the lesions and map them in the genome of postmitotic neurons.

The core of works reported by Reid et al. [6] and Wu et al. [7] is a sequencing technique to map the sites of DNA repair synthesis in the genome by capturing the non-replicative incorporation of nucleoside analog 5-ethynyl-2’-deoxyuridine (EdU). The methods are designated as Repair-seq and synthesis associated with repair sequencing (SAR-seq) by Reid et al. and Wu et al., respectively. They applied their new method to human embryonic stem cell-induced neurons (ESC-iNs) and postmitotic glutamatergic neurons derived from induced pluripotent stem cells (iPSCs) (i3Neurons). Wu et al. also observed SAR-seq peaks in primary rat neurons ruling out the possibility of an artifact of iPSC differentiation. On the other hand, Wu et al. did not detect incorporation of EdU in skeletal muscle cells differentiated from iPSCs (iMuscle) or G0-arrested pre-B cells. Both studies reached the same conclusion that postmitotic neurons accumulate an unexpectedly high level of recurrent repair synthesis at neuronal enhancers of genes required for identity and functionality. Wu et al. further uncovered the SAR-seq peaks coincide with the reads of ChIP-seq for ADP-ribose and XRCC1, indicating that SSBs are the causative lesions of recurrent repair synthesis. Wu et al. also devised a technique designated as S1 END-seq by modifying previously reported END-seq, which enabled locating endogenous SSBs with much higher resolution (at single-nucleotide resolution) than did SAR-seq and demonstrated that CpG dinucleotides were highly enriched at SAR sites.

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