Genomic context influences translesion synthesis DNA polymerase-dependent mechanisms of micronuclei induction by G-quadruplexes.

IF 7.5 1区生物学 Q1 CELL BIOLOGY

Cell reports Pub Date : 2025-05-10 DOI:10.1016/j.celrep.2025.115706

Simona Pepe, Federico Guerra, Marco Russo, Renée C Duardo, Giovanni Capranico

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引用次数: 0

Abstract

Guanine quadruplexes (G4s) are non-canonical DNA structures that can trigger micronuclei (MNi). Mechanisms of micronuclei formation by G4s are not fully understood. Here, we show that G4 stabilization can trigger cell-cycle-phase-specific mechanisms of replication fork stalling and DNA synthesis restart dependent on translesion synthesis (TLS) DNA polymerases (Pols). Fork stalling is caused by G-loops and high transcription during early S only. Moreover, while induction of micronuclei is dependent on DNA Pol η throughout S phase, primase and DNA-directed polymerase (PrimPol) is required in late S only. DNA breakage is not an immediate response to stabilized G4s but rather a consequence of persistent G4-mediated replication stress. Thus, different modes of fork stalling and restart, based on genomic context and TLS Pols, avoid immediate DNA breakage at stalled forks but at the expense of a risk of later mitotic chromosomal instability. The insights can lead to the development of more effective therapies for cancer and neurological diseases.

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基因组环境影响翻译合成DNA聚合酶依赖机制的微核诱导的g -四联体。

鸟嘌呤四联体（G4s）是一种非规范的DNA结构，可以触发微核（MNi）。G4s形成微核的机制尚不完全清楚。在这里，我们发现G4稳定可以触发细胞周期阶段特异性的复制叉停止和DNA合成重启机制，依赖于翻译合成（TLS） DNA聚合酶（pol）。叉子失速是由g环和S早期的高转录引起的。此外，虽然微核的诱导依赖于整个S期的DNA Pol η，但仅在S期后期才需要引物酶和DNA定向聚合酶（PrimPol）。DNA断裂不是对稳定的g4的直接反应，而是持续的g4介导的复制应激的结果。因此，基于基因组背景和TLS pol的不同分叉熄火和重启模式，避免了在熄火分叉处立即发生DNA断裂，但代价是随后有丝分裂染色体不稳定的风险。这些见解可以导致开发更有效的治疗癌症和神经系统疾病的方法。

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

Cell reports CELL BIOLOGY-

CiteScore

13.80

自引率

1.10%

发文量

1305

审稿时长

77 days

期刊介绍： Cell Reports publishes high-quality research across the life sciences and focuses on new biological insight as its primary criterion for publication. The journal offers three primary article types: Reports, which are shorter single-point articles, research articles, which are longer and provide deeper mechanistic insights, and resources, which highlight significant technical advances or major informational datasets that contribute to biological advances. Reviews covering recent literature in emerging and active fields are also accepted. The Cell Reports Portfolio includes gold open-access journals that cover life, medical, and physical sciences, and its mission is to make cutting-edge research and methodologies available to a wide readership. The journal's professional in-house editors work closely with authors, reviewers, and the scientific advisory board, which consists of current and future leaders in their respective fields. The advisory board guides the scope, content, and quality of the journal, but editorial decisions are independently made by the in-house scientific editors of Cell Reports.