REV1 coordinates a multi-faceted tolerance response to DNA alkylation damage and prevents chromosome shattering in Drosophila melanogaster.

IF 4 2区 生物学 Q1 GENETICS & HEREDITY
PLoS Genetics Pub Date : 2024-07-29 eCollection Date: 2024-07-01 DOI:10.1371/journal.pgen.1011181
Varandt Khodaverdian, Tokio Sano, Lara R Maggs, Gina Tomarchio, Ana Dias, Mai Tran, Connor Clairmont, Mitch McVey
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引用次数: 0

Abstract

When replication forks encounter damaged DNA, cells utilize damage tolerance mechanisms to allow replication to proceed. These include translesion synthesis at the fork, postreplication gap filling, and template switching via fork reversal or homologous recombination. The extent to which these different damage tolerance mechanisms are utilized depends on cell, tissue, and developmental context-specific cues, the last two of which are poorly understood. To address this gap, we have investigated damage tolerance responses in Drosophila melanogaster. We report that tolerance of DNA alkylation damage in rapidly dividing larval tissues depends heavily on translesion synthesis. Furthermore, we show that the REV1 protein plays a multi-faceted role in damage tolerance in Drosophila. Larvae lacking REV1 are hypersensitive to methyl methanesulfonate (MMS) and have highly elevated levels of γ-H2Av (Drosophila γ-H2AX) foci and chromosome aberrations in MMS-treated tissues. Loss of the REV1 C-terminal domain (CTD), which recruits multiple translesion polymerases to damage sites, sensitizes flies to MMS. In the absence of the REV1 CTD, DNA polymerases eta and zeta become critical for MMS tolerance. In addition, flies lacking REV3, the catalytic subunit of polymerase zeta, require the deoxycytidyl transferase activity of REV1 to tolerate MMS. Together, our results demonstrate that Drosophila prioritize the use of multiple translesion polymerases to tolerate alkylation damage and highlight the critical role of REV1 in the coordination of this response to prevent genome instability.

REV1 在黑腹果蝇中协调对 DNA 烷基化损伤的多方面耐受反应,并防止染色体破碎。
当复制叉遇到受损 DNA 时,细胞会利用损伤耐受机制使复制继续进行。这些机制包括在分叉处进行转座子合成、复制后间隙填充以及通过分叉逆转或同源重组进行模板切换。这些不同的损伤耐受机制在多大程度上得到利用取决于细胞、组织和发育环境的特异性线索,而对后两种线索的了解还很不够。为了填补这一空白,我们研究了黑腹果蝇的损伤耐受反应。我们报告说,在快速分裂的幼虫组织中,DNA烷基化损伤耐受性在很大程度上取决于转座子的合成。此外,我们还发现 REV1 蛋白在果蝇的损伤耐受中发挥着多方面的作用。缺乏REV1的幼虫对甲基磺酸盐(MMS)过敏,在MMS处理过的组织中,γ-H2Av(果蝇γ-H2AX)病灶和染色体畸变水平极高。REV1的C端结构域(CTD)能将多个转座聚合酶募集到损伤位点,而REV1 C端结构域的缺失会使果蝇对MMS过敏。在缺少 REV1 CTD 的情况下,DNA 聚合酶 eta 和 zeta 成为耐受 MMS 的关键。此外,缺乏聚合酶zeta的催化亚基REV3的苍蝇需要REV1的脱氧胞苷酸转移酶活性才能耐受MMS。总之,我们的研究结果表明果蝇会优先使用多种转座聚合酶来耐受烷基化损伤,并强调了 REV1 在协调这种反应以防止基因组不稳定中的关键作用。
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
PLoS Genetics
PLoS Genetics GENETICS & HEREDITY-
自引率
2.20%
发文量
438
期刊介绍: PLOS Genetics is run by an international Editorial Board, headed by the Editors-in-Chief, Greg Barsh (HudsonAlpha Institute of Biotechnology, and Stanford University School of Medicine) and Greg Copenhaver (The University of North Carolina at Chapel Hill). Articles published in PLOS Genetics are archived in PubMed Central and cited in PubMed.
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