Division of Molecular Biophysics and Integrated Bioimaging, Lawrence Berkeley National Laboratory, Berkeley, CA, USA.
Department of Environmental Health, John B Little Centre for Radiation Sciences, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
Nat Commun. 2024 Sep 4;15(1):7726. doi: 10.1038/s41467-024-51906-5.
We lack the fundamental information needed to understand how DNA damage in the brain is generated and how it is controlled over a lifetime in the absence of replication check points. To address these questions, here, we integrate cell-type and region-specific features of DNA repair activity in the normal brain. The brain has the same repair proteins as other tissues, but normal, canonical repair activity is unequal and is characterized by high base excision repair (BER) and low double strand break repair (DSBR). The natural imbalance creates conditions where single strand breaks (SSBs) can convert to double strand breaks (DSBs) and reversibly switch between states in response to oxidation both in vivo and in vitro. Our data suggest that, in a normal background of repair, SSBs and DSBs are in an equilibrium which is pushed or pulled by metabolic state. Interconversion of SSB to DSBs provides a physiological check point, which would allow the formation of unrepaired DSBs for productive functions, but would also restrict them from exceeding tolerable limits.
我们缺乏基本的信息来理解大脑中的 DNA 损伤是如何产生的，以及在没有复制检查点的情况下，它如何在一生中得到控制。为了解决这些问题，我们在这里整合了正常大脑中细胞类型和区域特异性的 DNA 修复活性特征。大脑具有与其他组织相同的修复蛋白，但正常的、规范的修复活性是不均衡的，其特点是碱基切除修复（BER）高，双链断裂修复（DSBR）低。这种自然的不平衡创造了这样的条件，即单链断裂（SSB）可以转化为双链断裂（DSB），并在体内和体外的氧化作用下，在不同状态之间可逆地切换。我们的数据表明，在修复的正常背景下，SSB 和 DSB 处于一种平衡状态，这种平衡状态可以通过代谢状态来推动或拉动。SSB 向 DSB 的转化提供了一个生理检查点，它可以允许未修复的 DSB 形成有生产力的功能，但也会限制它们超过可容忍的极限。
