2023-07-26 カリフォルニア大学リバーサイド校(UCR)
◆ミトコンドリアは細胞のエネルギー生産に関与しており、その機能が低下すると細胞損傷や臓器の不全が引き起こされることがあります。TFAMはDNAを切断し、損傷を受けた遺伝子物質をクリーンアップする役割を果たし、ミトコンドリアの正常な機能をサポートします。これにより、ミトコンドリア疾患の診断に役立ち、早期治療の提供が可能になることが期待されています。
<関連情報>
- https://news.ucr.edu/articles/2023/07/26/ray-hope-mitochondrial-diseases-proteins-surprising-second-role
- https://pubs.acs.org/doi/10.1021/acschembio.3c00047
Kミトコンドリア転写因子Aの主要アミノ酸残基がアベーシック(AP)部位のダイナミクスと相乗してAP-リアーゼ反応を促進することを発見 ey Amino Acid Residues of Mitochondrial Transcription Factor A Synergize with Abasic (AP) Site Dynamics To Facilitate AP-Lyase Reactions
Wenxin Zhao, Wenyan Xu, Jin Tang, Shivansh Kaushik, Chia-En A. Chang, and Linlin Zhao
ACS Chemical Biology Published:March 17, 2023
DOI:https://doi.org/10.1021/acschembio.3c00047
Abstract
Human mitochondrial DNA (mtDNA) encodes 37 essential genes and plays a critical role in mitochondrial and cellular functions. mtDNA is susceptible to damage by endogenous and exogenous chemicals. Damaged mtDNA molecules are counteracted by the redundancy, repair, and degradation of mtDNA. In response to difficult-to-repair or excessive amounts of DNA lesions, mtDNA degradation is a crucial mitochondrial genome maintenance mechanism. Nevertheless, the molecular basis of mtDNA degradation remains incompletely understood. Recently, mitochondrial transcription factor A (TFAM) has emerged as a factor in degrading damaged mtDNA containing abasic (AP) sites. TFAM has AP-lyase activity, which cleaves DNA at AP sites. Human TFAM and its homologs contain a higher abundance of Glu than that of the proteome. To decipher the role of Glu in TFAM-catalyzed AP-DNA cleavage, we constructed TFAM variants and used biochemical assays, kinetic simulations, and molecular dynamics (MD) simulations to probe the functional importance of E187 near a key residue K186. Our previous studies showed that K186 is a primary residue to cleave AP-DNA via Schiff base chemistry. Here, we demonstrate that E187 facilitates β-elimination, key to AP-DNA strand scission. MD simulations showed that extrahelical confirmation of the AP lesion and the flexibility of E187 in TFAM-DNA complexes facilitate AP-lyase reactions. Together, highly abundant Lys and Glu residues in TFAM promote AP-DNA strand scission, supporting the role of TFAM in AP-DNA turnover and implying the breadth of this process across different species.
