Exonuclease action of replicative polymerase gamma drives damage-induced mitochondrial DNA clearance.

IF 6.2 1区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY EMBO Reports Pub Date : 2025-03-01 Epub Date: 2025-01-31 DOI:10.1038/s44319-025-00380-1

Akshaya Seshadri, Anjana Badrinarayanan

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Abstract

Mitochondrial DNA (mtDNA) replication is essential for mitochondrial function. This is carried out by a dedicated DNA polymerase gamma, with 5'-3' polymerase and 3'-5' proofreading/ exonuclease activity. Perturbations to either property can have pathological consequences. Predominant sources for replication stress are DNA lesions, such as those induced by oxidative damage. How mtDNA lesions affect the polymerase activity and mtDNA stability in vivo is not fully understood. To address this, we induce mtDNA-specific damage in S. cerevisiae. We observe that mtDNA damage results in significant mtDNA loss. This loss occurs independent of cell cycle progression or cell division, suggesting an active mechanism for damaged mtDNA clearance. We implicate the 3'-5' exonuclease activity of the mtDNA polymerase in this clearance, with rates of loss being affected by cellular dNTP levels. Overall, our findings reveal context-dependent, selective regulation of two critical but opposing functions of polymerase gamma to ensure mitochondrial genome integrity.

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复制聚合酶的外切酶作用驱动损伤诱导的线粒体DNA清除。

线粒体DNA （mtDNA）的复制对线粒体功能至关重要。这是由专用的DNA聚合酶γ进行的，具有5‘-3’聚合酶和3‘-5’校对/外切酶活性。对任何性质的扰动都可能产生病理后果。复制应激的主要来源是DNA损伤，如氧化损伤引起的DNA损伤。mtDNA损伤如何影响体内聚合酶活性和mtDNA稳定性尚不完全清楚。为了解决这个问题，我们在酿酒葡萄球菌中诱导了mtdna特异性损伤。我们观察到mtDNA损伤导致显著的mtDNA丢失。这种损失与细胞周期进程或细胞分裂无关，表明受损mtDNA清除的积极机制。我们认为mtDNA聚合酶的3‘-5’外切酶活性与这种清除有关，其损失率受细胞dNTP水平的影响。总的来说，我们的研究结果揭示了聚合酶γ的两个关键但相反的功能依赖于环境的选择性调节，以确保线粒体基因组的完整性。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

EMBO Reports 生物-生化与分子生物学

CiteScore

11.20

自引率

1.30%

发文量

267

审稿时长

1 months

期刊介绍： EMBO Reports is a scientific journal that specializes in publishing research articles in the fields of molecular biology, cell biology, and developmental biology. The journal is known for its commitment to publishing high-quality, impactful research that provides novel physiological and functional insights. These insights are expected to be supported by robust evidence, with independent lines of inquiry validating the findings. The journal's scope includes both long and short-format papers, catering to different types of research contributions. It values studies that: Communicate major findings: Articles that report significant discoveries or advancements in the understanding of biological processes at the molecular, cellular, and developmental levels. Confirm important findings: Research that validates or supports existing knowledge in the field, reinforcing the reliability of previous studies. Refute prominent claims: Studies that challenge or disprove widely accepted ideas or hypotheses in the biosciences, contributing to the correction and evolution of scientific understanding. Present null data: Papers that report negative results or findings that do not support a particular hypothesis, which are crucial for the scientific process as they help to refine or redirect research efforts. EMBO Reports is dedicated to maintaining high standards of scientific rigor and integrity, ensuring that the research it publishes contributes meaningfully to the advancement of knowledge in the life sciences. By covering a broad spectrum of topics and encouraging the publication of both positive and negative results, the journal plays a vital role in promoting a comprehensive and balanced view of scientific inquiry.