Awoyomi Ololade Folajimi, Gorospe Choco Michael, Das Biswajit, Mishra Pradeep, Sharma Sushma, Diachenko Olena, Nilsson Anna Karin, Tran Phong, Wanrooij Paulina H, Chabes Andrei
Department of Medical Biochemistry and Biophysics, Umeå University, Umeå SE 90187, Sweden.
Proc Natl Acad Sci U S A. 2025 Apr 22;122(16):e2503531122. doi: 10.1073/pnas.2503531122. Epub 2025 Apr 17.
Mitochondrial DNA (mtDNA) replication requires a steady supply of deoxyribonucleotides (dNTPs), synthesized de novo by ribonucleotide reductase (RNR). In nondividing cells, RNR consists of RRM1 and RRM2B subunits. Mutations in cause mtDNA depletion syndrome, linked to muscle weakness, neurological decline, and early mortality. The impact of RRM2B deficiency on dNTP pools in nondividing tissues remains unclear. Using a mouse knockout model, we demonstrate that RRM2B deficiency selectively depletes dATP and dGTP, while dCTP and dTTP levels remain stable or increase. This depletion pattern resembles the effects of hydroxyurea, an inhibitor that reduces overall RNR activity. Mechanistically, we propose that the depletion of dATP and dGTP arises from their preferred degradation by the dNTPase SAMHD1 and the lower production rate of dATP by RNR. Identifying dATP and dGTP depletion as a hallmark of RRM2B deficiency provides insights for developing nucleoside bypass therapies to alleviate the effects of RRM2B mutations.
线粒体DNA（mtDNA）复制需要由核糖核苷酸还原酶（RNR）从头合成的脱氧核糖核苷酸（dNTP）的稳定供应。在非分裂细胞中，RNR由RRM1和RRM2B亚基组成。RRM2B突变会导致mtDNA耗竭综合征，与肌肉无力、神经功能衰退和早期死亡有关。RRM2B缺陷对非分裂组织中dNTP库的影响尚不清楚。利用小鼠基因敲除模型，我们证明RRM2B缺陷会选择性地消耗dATP和dGTP，而dCTP和dTTP水平保持稳定或升高。这种消耗模式类似于羟基脲的作用，羟基脲是一种降低整体RNR活性的抑制剂。从机制上讲，我们认为dATP和dGTP的消耗源于dNTP酶SAMHD1对它们的优先降解以及RNR产生dATP的较低速率。将dATP和dGTP消耗确定为RRM2B缺陷的标志，为开发核苷旁路疗法以减轻RRM2B突变的影响提供了思路。
