Center for Chromosome Stability, University of Copenhagen, Copenhagen, Denmark.
Institute of Cancer Research, London, UK.
Nat Struct Mol Biol. 2020 May;27(5):424-437. doi: 10.1038/s41594-020-0408-6. Epub 2020 May 11.
Oncogene activation during tumorigenesis generates DNA replication stress, a known driver of genome rearrangements. In response to replication stress, certain loci, such as common fragile sites and telomeres, remain under-replicated during interphase and subsequently complete locus duplication in mitosis in a process known as 'MiDAS'. Here, we demonstrate that RTEL1 (regulator of telomere elongation helicase 1) has a genome-wide role in MiDAS at loci prone to form G-quadruplex-associated R-loops, in a process that is dependent on its helicase function. We reveal that SLX4 is required for the timely recruitment of RTEL1 to the affected loci, which in turn facilitates recruitment of other proteins required for MiDAS, including RAD52 and POLD3. Our findings demonstrate that RTEL1 is required for MiDAS and suggest that RTEL1 maintains genome stability by resolving conflicts that can arise between the replication and transcription machineries.
癌基因在肿瘤发生过程中的激活会产生 DNA 复制应激，这是基因组重排的已知驱动因素。为了应对复制应激，某些基因座，如常见的脆性位点和端粒，在有丝分裂期间仍然复制不足，并在有丝分裂中通过称为“MiDAS”的过程完成基因座的重复。在这里，我们证明 RTEL1（端粒延伸解旋酶 1 的调节剂）在易形成 G-四联体相关 R-环的基因座的 MiDAS 中具有全基因组作用，该过程依赖于其解旋酶功能。我们揭示了 SLX4 对于 RTEL1 及时募集到受影响的基因座是必需的，这反过来又促进了其他 MiDAS 所需蛋白的募集，包括 RAD52 和 POLD3。我们的研究结果表明，RTEL1 是 MiDAS 所必需的，并表明 RTEL1 通过解决复制和转录机制之间可能出现的冲突来维持基因组稳定性。
