人类双链断裂修复的综合基因目录

IF 45.8 1区综合性期刊 Q1 MULTIDISCIPLINARY SCIENCES

Science Pub Date : 2025-10-02 DOI:10.1126/science.adr5048

Ernesto López de Alba, Israel Salguero, Daniel Giménez-Llorente, Javier Montes-Torres, Ángel Fernández-Sanromán, Ester Casajús-Pelegay, José Terrón-Bautista, Jonathan Barroso-González, Juan A. Bernal, Geoff Macintyre, Rafael Fernández-Leiro, Ana Losada, Felipe Cortés-Ledesma

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引用次数: 0

摘要

DNA序列结果的分析提供了双链断裂（DSB）修复机制的分子见解。利用全基因组敲除文库中cas9诱导的插入和缺失（indels）的平行池内分析，我们提出了一个全面的目录，评估了几乎每个人类基因对DSB修复结果的影响。repairrome资源揭示了参与DSB修复的未知机制、途径和因素，包括XLF和PAXX的相反作用，cas9诱导的多核苷酸插入的分子解释，HLTF在cas9诱导的DSB修复中的功能，SAGA复合物在微同源介导的末端连接中的参与，以及与VHL丢失、肾癌和缺氧相关的indel突变特征。这些结果证明了repairrome在推动DSB修复、CRISPR-Cas基因编辑和癌症突变特征病因学的未来发现方面的潜力。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

A comprehensive genetic catalog of human double-strand break repair

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A comprehensive genetic catalog of human double-strand break repair

The analysis of DNA sequence outcomes provides molecular insights into double-strand break (DSB) repair mechanisms. Using parallel in-pool profiling of Cas9-induced insertions and deletions (indels) within a genome-wide knockout library, we present a comprehensive catalog that assesses the influence of nearly every human gene on DSB repair outcomes. This REPAIRome resource uncovers uncharacterized mechanisms, pathways, and factors involved in DSB repair, including opposing roles for XLF and PAXX, a molecular explanation for Cas9-induced multinucleotide insertions, HLTF functions in Cas9-induced DSB repair, the involvement of the SAGA complex in microhomology-mediated end joining, and an indel mutational signature linked to VHL loss, renal carcinoma, and hypoxia. These results exemplify the potential of REPAIRome to drive future discoveries in DSB repair, CRISPR-Cas gene editing and the etiology of cancer mutational signatures.

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来源期刊

Science 综合性期刊-综合性期刊

CiteScore

61.10

自引率

0.90%

发文量

审稿时长

2.1 months

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