Camps Manel, Loeb Lawrence A
The Joseph Gottstein Memorial Cancer Research Laboratory, Department of Pathology, University of Washington, Seattle, WA 98195-7705, USA.
Front Biosci. 2005 Jan 1;10:689-98. doi: 10.2741/1564.
Blocks in replication result from impediments to the advancing replication machinery and are lethal if not resolved. The replication fork must be reassembled for DNA synthesis to proceed. Fork assembly outside the chromosomal origin of replication (oriC) is mediated by recombination or via a helicase-dependent pathway. ColE1 plasmid origins of replication and oriK sites initiate primosome assembly by an RNA-DNA hybrid structure known as R-loop. We review evidence suggesting that R-loops are frequent during normal cell growth and that R-loops are critical for the maintenance of genome integrity. We propose that downstream of a replication block, RNA at R-loops is extended by DNA polymerase I, opening up the DNA duplex and leading to the recruitment of the replisome. This would allow replication to proceed while the original block is repaired or bypassed. Unlike recombination and helicase-dependent fork restoration, this mechanism would operate preferentially in transcribed areas of the genome, which are known to be particularly susceptible to DNA damage. Our model emphasizes the intimate relationship between transcription and repair, offers a unifying interpretation of phenotypes attributed to bacterial strains deficient in R-loop fork assembly, and calls for a renewed focus on R-loop formation and regulation.
复制过程中的阻碍源于前进的复制机制所遇到的障碍，若不解决则具有致死性。必须重新组装复制叉才能继续进行DNA合成。在染色体复制起点（oriC）之外的复制叉组装是通过重组或依赖解旋酶的途径介导的。ColE1质粒复制起点和oriK位点通过一种称为R环的RNA-DNA杂交结构启动引发体组装。我们综述了相关证据，这些证据表明R环在正常细胞生长过程中很常见，并且对维持基因组完整性至关重要。我们提出，在复制阻碍的下游，R环处的RNA由DNA聚合酶I延伸，打开DNA双链并导致复制体的招募。这将使复制能够继续进行，同时修复或绕过原始阻碍。与重组和解旋酶依赖的复制叉恢复不同，这种机制将优先在基因组的转录区域起作用，已知该区域特别容易受到DNA损伤。我们的模型强调了转录与修复之间的密切关系，对归因于R环复制叉组装缺陷的细菌菌株的表型提供了统一的解释，并呼吁重新关注R环的形成和调控。
