DNA damage checkpoint activation affects peptidoglycan synthesis and late divisome components in Bacillus subtilis.
DNA damage checkpoint activation affects peptidoglycan synthesis and late divisome components in Bacillus subtilis.
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DOI：
10.1111/mmi.14765
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发表时间：
2021-08
影响因子：
3.6
通讯作者：
Simmons LA
中科院分区：
文献类型：
--
作者：
Masser EA;Burby PE;Hawkins WD;Gustafson BR;Lenhart JS;Simmons LA
在正常的 DNA 复制过程中，所有细胞的遗传物质都会受到损害。因此，生物体已经发展出反应途径，为细胞在细胞分裂发生之前完成 DNA 修复提供时间。在枯草芽孢杆菌中，已证实 SOS 诱导的细胞分裂抑制剂 YneA 可在基因毒性应激后阻止细胞分裂；然而，目前还不清楚 YneA 如何执行检查点。在这里，我们鉴定了破坏 YneA 活性的突变和对 YneA 诱导的检查点无效的突变。我们发现 YneA C 端截短突变体和 LysM 肽聚糖结合域内或附近的点突变体使 YneA 无法执行检查点。此外，我们开发了一种遗传方法，分离出 ftsW 基因中的突变，完全绕过检查点执行，同时还发现 YneA 与晚期分裂体成分 FtsL、Pbp2b 和 Pbp1 相互作用。 FtsW 变体的表征导致 DNA 损伤反应期间细胞显着缩短，表明细胞分裂启动过度活跃并绕过了 YneA 强制的 DNA 损伤检查点。根据我们的结果，我们提出了一个模型，其中 YneA 通过结合肽聚糖并干扰迟到的分裂体成分之间的相互作用，从而导致 DNA 损伤检查点激活，从而抑制隔膜细胞壁的合成。在正常细胞分裂和非 DNA 损伤条件下，肽聚糖聚合酶 FtsW 在隔膜细胞壁合成过程中将脂质 II 组装成肽聚糖。在这项工作中，我们提出了一种新模型来解释 YneA 如何阻止枯草芽孢杆菌的细胞分裂。 DNA 损伤后，SOS 诱导的细胞分裂抑制剂 YneA 与晚期分裂体蛋白 FtsL、Pbp2b 和 Pbp1 相互作用，并通过其 LysM 结构域 (LysM) 结合肽聚糖，抑制隔膜细胞壁合成并阻止细胞分裂。
During normal DNA replication, all cells encounter damage to their genetic material. As a result, organisms have developed response pathways that provide time for the cell to complete DNA repair before cell division occurs. In Bacillus subtilis, it is well established that the SOS-induced cell division inhibitor YneA blocks cell division after genotoxic stress; however, it remains unclear how YneA enforces the checkpoint. Here, we identify mutations that disrupt YneA activity and mutations that are refractory to the YneA-induced checkpoint. We found that YneA C-terminal truncation mutants and point mutants in or near the LysM peptidoglycan binding domain rendered YneA incapable of checkpoint enforcement. In addition, we developed a genetic method which isolated mutations in the ftsW gene that completely bypassed checkpoint enforcement while also finding that YneA interacts with late divisome components FtsL, Pbp2b and Pbp1. Characterization of an FtsW variant resulted in considerably shorter cells during the DNA damage response indicative of hyperactive initiation of cell division and bypass of the YneA enforced DNA damage checkpoint. With our results, we present a model where YneA inhibits septal cell wall synthesis by binding peptidoglycan and interfering with interaction between late arriving divisome components causing DNA damage checkpoint activation. During normal cell division and non-DNA damaging conditions, the peptidoglycan polymerase FtsW assembles Lipid II into peptidoglycan during septal cell wall synthesis. In this work, we propose a new model for how YneA halts cell division in Bacillus subtilis. Following DNA damage, the SOS-induced cell division inhibitor YneA interacts with the late divisome proteins FtsL, Pbp2b and Pbp1 as well as binds peptidoglycan through its LysM domain (LysM), inhibiting septal cell wall synthesis and preventing cell division.
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