Linking transcription with DNA repair, damage tolerance, and genome duplication.
Linking transcription with DNA repair, damage tolerance, and genome duplication.
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将转录与 DNA 修复、损伤耐受和基因组复制联系起来。
DOI：
10.1073/pnas.1010659107
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发表时间：
2010
影响因子：
11.1
通讯作者：
McGlynn P
中科院分区：
文献类型：
--
作者：
McGlynn P
通过RNA聚合酶（RNAP）进行的基因转录远非一帆风顺。RNAP的模板序列依赖性暂停不仅经常发生（1），转录链内的病变对RNAP的继续运动构成主要障碍，对基因表达具有潜在的灾难性后果（2）。更糟糕的是，这种停滞的转录复合物掩盖了DNA损伤，使其无法被修复系统识别和清除（3）（图1A）。转录偶联修复（TCR）通过将修复酶募集到被病变阻断的RNAP来提供对该问题的解决方案，结果是优先修复表达基因的转录链内的DNA损伤（4，5）。大肠杆菌中的转录修复偶联因子Mfd是这种偶联的最佳表征实例，并为其他生物体中的TCR提供了范例（6）（图1B）。PNAS的一份报告表明，还存在第二种非常不同的TCR类型。Cohen等人(7)证明转录延伸因子NusA促进E.大肠杆菌，提供了一个解释的细胞缺乏Mfd的轻度损伤敏感性，并建议TCR的第二种机制，可以在其他生物体中运作。他们的工作还指出，NusA是协调转录、DNA修复、损伤耐受和基因组稳定性的核心参与者。NusA的这种新鉴定的功能是出乎意料的。NusA长期以来被认为是一种RNAP延伸因子，可调节转录暂停和终止（8）。步行者实验室（9，10）最近的工作也确定了NusA在募集跨损伤合成DNA聚合酶DinB到转录复合物中的可能作用。翻译合成（TLS）提供了损伤耐受的重要机制，其中具有降低保真度的专门DNA聚合酶复制通过DNA损伤，否则这些DNA损伤阻断用于复制大部分基因组的高保真复制聚合酶。步行者和同事提出了一个模型，其中由于复制叉的通过和/或失败的DNA修复，在与DNA损伤相对的基因转录链内出现缺口（9，10）。这种缺口阻断了RNAP转录的进程，这一点由Cohen et al. (7)但是DinB的募集可能允许DNA合成通过损伤并修复差距，从而完成转录。因此，NusA可能在称为“转录偶联跨损伤合成”的过程中通过转录机制促进DNA损伤耐受性（9）。
The transcription of genes by RNA polymerases (RNAPs) is far from a smooth ride. Not only is template sequence-dependent pausing of RNAPs a frequent occurrence (1), lesions within the transcribed strand present major barriers to continued movement of RNAPs, with potentially disastrous consequences for gene expression (2). To make matters worse, such stalled transcription complexes mask the DNA damage from recognition and removal by repair systems (3)(Fig. 1A). Transcriptioncoupled repair (TCR) provides a solution to this problem by recruiting repair enzymes to RNAPs blocked by lesions, the outcome being preferential repair of DNA damage within the transcribed strand of expressed genes (4, 5). The transcription repair coupling factor in Escherichia coli, Mfd, is the best-characterized example of such coupling and has provided a paradigm for TCR in other organisms (6)(Fig. 1B). A report in PNAS indicates that a second, very different, type of TCR also exists. Cohen et al.(7) demonstrate that a transcription elongation factor, NusA, promotes an Mfd-independent pathway of TCR in E. coli, providing an explanation for the mild damage sensitivity of cells lacking Mfd and suggesting that a second mechanism of TCR could be operative in other organisms. Their work also points to NusA as being a central player in coordination of transcription, DNA repair, damage tolerance, and genome stability. This newly identified function of NusA is unexpected. NusA has long been known to be an RNAP elongation factor that modulates transcription pausing and termination (8). Recent work by the Walker laboratory (9, 10) also identified a possible role of NusA in recruiting a translesion synthesis DNA polymerase, DinB, to transcription complexes. Translesion synthesis (TLS) provides an important mechanism of damage tolerance in which specialized DNA polymerases with reduced fidelity replicate past DNA lesions that otherwise block the high-fidelity replicative polymerases used to duplicate most of the genome. Walker and colleagues suggested a model in which gaps arise within the transcribed strand of genes opposite a DNA lesion as a result of passage of a replication fork and/or abortive DNA repair (9, 10). Such gaps block progression of transcribing RNAPs, confirmed byCohen et al.(7), but recruitment of DinB might allow DNA synthesis past the lesion and repair of the gap, allowing completion of transcription. NusA might therefore promote tolerance of DNA damage by the transcription machinery in a process termed “transcription-coupled translesion synthesis”(9).