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Defects in the GINS complex increase the instability of repetitive sequences via a recombination-dependent mechanism.
PLOS Genetics ( IF 4.0 ) Pub Date : 2019-12-09 , DOI: 10.1371/journal.pgen.1008494 Malgorzata Jedrychowska 1 , Milena Denkiewicz-Kruk 1 , Malgorzata Alabrudzinska 1 , Adrianna Skoneczna 1 , Piotr Jonczyk 1 , Michal Dmowski 1 , Iwona J Fijalkowska 1
PLOS Genetics ( IF 4.0 ) Pub Date : 2019-12-09 , DOI: 10.1371/journal.pgen.1008494 Malgorzata Jedrychowska 1 , Milena Denkiewicz-Kruk 1 , Malgorzata Alabrudzinska 1 , Adrianna Skoneczna 1 , Piotr Jonczyk 1 , Michal Dmowski 1 , Iwona J Fijalkowska 1
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Faithful replication and repair of DNA lesions ensure genome maintenance. During replication in eukaryotic cells, DNA is unwound by the CMG helicase complex, which is composed of three major components: the Cdc45 protein, Mcm2-7, and the GINS complex. The CMG in complex with DNA polymerase epsilon (CMG-E) participates in the establishment and progression of the replisome. Impaired functioning of the CMG-E was shown to induce genomic instability and promote the development of various diseases. Therefore, CMG-E components play important roles as caretakers of the genome. In Saccharomyces cerevisiae, the GINS complex is composed of the Psf1, Psf2, Psf3, and Sld5 essential subunits. The Psf1-1 mutant form fails to interact with Psf3, resulting in impaired replisome assembly and chromosome replication. Here, we show increased instability of repeat tracts (mononucleotide, dinucleotide, trinucleotide and longer) in yeast psf1-1 mutants. To identify the mechanisms underlying this effect, we analyzed repeated sequence instability using derivatives of psf1-1 strains lacking genes involved in translesion synthesis, recombination, or mismatch repair. Among these derivatives, deletion of RAD52, RAD51, MMS2, POL32, or PIF1 significantly decreased DNA repeat instability. These results, together with the observed increased amounts of single-stranded DNA regions and Rfa1 foci suggest that recombinational mechanisms make important contributions to repeat tract instability in psf1-1 cells. We propose that defective functioning of the CMG-E complex in psf1-1 cells impairs the progression of DNA replication what increases the contribution of repair mechanisms such as template switch and break-induced replication. These processes require sequence homology search which in case of a repeated DNA tract may result in misalignment leading to its expansion or contraction.
中文翻译：
GINS复合物中的缺陷通过依赖重组的机制增加了重复序列的不稳定性。
忠实地复制和修复DNA损伤可确保基因组的维持。在真核细胞中复制期间，DNA由CMG解旋酶复合物解链，该复合物由三个主要成分组成：Cdc45蛋白，Mcm2-7和GINS复合物。与DNA聚合酶epsilon（CMG-E）配合的CMG参与复制体的建立和发展。CMG-E的功能受损被证明可诱导基因组不稳定，并促进各种疾病的发展。因此，CMG-E成分作为基因组的看护者起着重要的作用。在酿酒酵母中，GINS复合物由Psf1，Psf2，Psf3和Sld5必需亚基组成。Psf1-1突变体形式无法与Psf3相互作用，从而导致复制体组装和染色体复制受损。这里，我们显示出酵母psf1-1突变体中重复区域（单核苷酸，二核苷酸，三核苷酸及更长）的不稳定性增加。为了确定这种作用的潜在机制，我们使用缺少参与跨病变合成，重组或错配修复的基因的psf1-1菌株的衍生物分析了重复的序列不稳定性。在这些衍生物中，RAD52，RAD51，MMS2，POL32或PIF1的缺失显着降低了DNA重复序列的不稳定性。这些结果，再加上观察到的单链DNA区域和Rfa1焦点数量的增加，表明重组机制对psf1-1细胞中的重复道不稳定性做出了重要贡献。我们提出，psf1-1细胞中CMG-E复合物的功能缺陷会损害DNA复制的进程，从而增加修复机制（如模板转换和断裂诱导的复制）的贡献。这些过程需要进行序列同源性检索，如果重复DNA片段，可能会导致序列比对，从而导致其扩增或收缩。
更新日期：2019-12-11
中文翻译：
GINS复合物中的缺陷通过依赖重组的机制增加了重复序列的不稳定性。
忠实地复制和修复DNA损伤可确保基因组的维持。在真核细胞中复制期间，DNA由CMG解旋酶复合物解链，该复合物由三个主要成分组成：Cdc45蛋白，Mcm2-7和GINS复合物。与DNA聚合酶epsilon（CMG-E）配合的CMG参与复制体的建立和发展。CMG-E的功能受损被证明可诱导基因组不稳定，并促进各种疾病的发展。因此，CMG-E成分作为基因组的看护者起着重要的作用。在酿酒酵母中，GINS复合物由Psf1，Psf2，Psf3和Sld5必需亚基组成。Psf1-1突变体形式无法与Psf3相互作用，从而导致复制体组装和染色体复制受损。这里，我们显示出酵母psf1-1突变体中重复区域（单核苷酸，二核苷酸，三核苷酸及更长）的不稳定性增加。为了确定这种作用的潜在机制，我们使用缺少参与跨病变合成，重组或错配修复的基因的psf1-1菌株的衍生物分析了重复的序列不稳定性。在这些衍生物中，RAD52，RAD51，MMS2，POL32或PIF1的缺失显着降低了DNA重复序列的不稳定性。这些结果，再加上观察到的单链DNA区域和Rfa1焦点数量的增加，表明重组机制对psf1-1细胞中的重复道不稳定性做出了重要贡献。我们提出，psf1-1细胞中CMG-E复合物的功能缺陷会损害DNA复制的进程，从而增加修复机制（如模板转换和断裂诱导的复制）的贡献。这些过程需要进行序列同源性检索，如果重复DNA片段，可能会导致序列比对，从而导致其扩增或收缩。
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