Weaver Tyler M, Ryan Benjamin J, Thompson Spencer H, Hussen Adil S, Spencer Jonah J, Xu Zhen, Schnicker Nicholas J, Freudenthal Bret D
Department of Biochemistry and Molecular Biology, University of Kansas Medical Center, Kansas City, KS, 66160, USA.
Department of Cancer Biology, University of Kansas Medical Center, Kansas City, KS, 66160, USA.
Nat Commun. 2025 Mar 17;16(1):2607. doi: 10.1038/s41467-025-57915-2.
Single-strand breaks (SSBs) are one of the most prevalent forms of DNA damage found in the chromatinized genome and are repaired by single-strand break repair (SSBR) or base excision repair (BER). DNA polymerase beta (Pol β) is the primary enzyme responsible for processing the 1-nt gap intermediate in chromatin during SSBR and BER. To date, the mechanism used by Pol β to process a 1-nt gap in the context of chromatin remains poorly understood. Here, we use biochemical assays and cryogenic electron microscopy (cryo-EM) to determine the kinetic and structural basis of gap-filling DNA synthesis in the nucleosome by Pol β. This work establishes that Pol β uses a global DNA sculpting mechanism for processing 1-nt gaps in the nucleosome during SSBR and BER, providing fundamental insight into DNA repair in chromatin.
单链断裂（SSBs）是染色质化基因组中最常见的DNA损伤形式之一，可通过单链断裂修复（SSBR）或碱基切除修复（BER）进行修复。DNA聚合酶β（Polβ）是在SSBR和BER过程中负责处理染色质中1个核苷酸间隙中间体的主要酶。迄今为止，Polβ在染色质环境中处理1个核苷酸间隙所使用的机制仍知之甚少。在这里，我们使用生化分析和低温电子显微镜（cryo-EM）来确定Polβ在核小体中进行填补间隙DNA合成的动力学和结构基础。这项工作表明，Polβ在SSBR和BER过程中使用一种全局DNA重塑机制来处理核小体中的1个核苷酸间隙，为染色质中的DNA修复提供了基本见解。
