Institute of Chemical Biology and Fundamental Medicine, Siberian Branch of Russian Academy of Sciences, 630090 Novosibirsk, Russia.
Department of Natural Sciences, Novosibirsk State University, 630090 Novosibirsk, Russia.
Int J Mol Sci. 2023 Mar 20;24(6):5892. doi: 10.3390/ijms24065892.
DNA polymerase β (Polβ) expression is essential for the cell's response to DNA damage that occurs during natural cellular processes. Polβ is considered the main reparative DNA polymerase, whose role is to fill the DNA gaps arising in the base excision repair pathway. Mutations in Polβ can lead to cancer, neurodegenerative diseases, or premature aging. Many single-nucleotide polymorphisms have been identified in the gene, but the consequences of these polymorphisms are not always clear. It is known that some polymorphic variants in the Polβ sequence reduce the efficiency of DNA repair, thereby raising the frequency of mutations in the genome. In the current work, we studied two polymorphic variants (G118V and R149I separately) of human Polβ that affect its DNA-binding region. It was found that each amino acid substitution alters Polβ's affinity for gapped DNA. Each polymorphic variant also weakens its binding affinity for dATP. The G118V variant was found to greatly affect Polβ's ability to fill gapped DNA and slowed the catalytic rate as compared to the wild-type enzyme. Thus, these polymorphic variants seem to decrease the ability of Polβ to maintain base excision repair efficiency.
DNA 聚合酶 β（Polβ）的表达对于细胞对自然细胞过程中发生的 DNA 损伤的反应至关重要。Polβ 被认为是主要的修复性 DNA 聚合酶，其作用是填补碱基切除修复途径中出现的 DNA 缺口。Polβ 的突变可导致癌症、神经退行性疾病或过早衰老。在基因中已经鉴定出许多单核苷酸多态性，但这些多态性的后果并不总是清楚。已知 Polβ 序列中的一些多态性变体降低了 DNA 修复的效率，从而增加了基因组中突变的频率。在当前的工作中，我们研究了影响其 DNA 结合区域的人类 Polβ 的两种多态性变体（分别为 G118V 和 R149I）。研究发现，每种氨基酸取代都会改变 Polβ 对缺口 DNA 的亲和力。每种多态性变体也会削弱其与 dATP 的结合亲和力。与野生型酶相比，G118V 变体极大地影响了 Polβ 填充缺口 DNA 的能力，并降低了催化速率。因此，这些多态性变体似乎降低了 Polβ 维持碱基切除修复效率的能力。
