RecQ helicases in the malaria parasite Plasmodium falciparum affect genome stability, gene expression patterns and DNA replication dynamics.
RecQ helicases in the malaria parasite Plasmodium falciparum affect genome stability, gene expression patterns and DNA replication dynamics.
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DOI：
10.1371/journal.pgen.1007490
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发表时间：
2018-07
期刊：
影响因子：
4.5
通讯作者：
Merrick CJ
中科院分区：
文献类型：
--
作者：
Claessens A;Harris LM;Stanojcic S;Chappell L;Stanton A;Kuk N;Veneziano-Broccia P;Sterkers Y;Rayner JC;Merrick CJ
疟原虫恶性疟原虫的基因组的大多数基因组都相对稳定。相关的VAR基因。恶性疟原虫，PFBLM和PFWRN中的解旋酶时，重组率增加了四倍，产生了染色体异常，嵌合var基因的高速率和许多微型介质，尤其是在已知的“脆弱地点”。鉴定抑制重组和维持基因组稳定性的基因，相反，突变率没有变化但是，PFBLM在转录水平上进行了突变，两种旋转酶显然调节了大量基因的转录，其中几百个基因（包括大量的VAR）在每个RECQ突变体中都显示了放松的表达。是一种可能升高的突变率的机制，通过测量RECQ突变叉中的DNA复制动力学来评估这一点。以两个突变体的速度升高，确认有效的DNA复制需要RECQ解旋酶。用于该病原体中的基因组进化。
人类疟疾是由疟原虫寄生虫引起的，大多数死亡率（每年近半百万人死亡）是由一个物种引起的，疟原虫是恶性疟原虫。 C，它包含富含高变量病毒相关基因的特定区域，这些基因的进化非常迅速地产生新的变化。逃避人类免疫系统并维持慢性感染的寄生虫，但是在分子水平上如何控制它，我们已经在寄生虫中确定了对基因组稳定性和基因组进化速度的巨大影响通过放松各种异常的DNA结构的功能，如果这失败了，那么基因组就会不稳定。结构受到影响，如果在不同的寄生虫菌株中表达了这种解旋酶，它可能会影响寄生虫有效生长和复制的能力，并完全逃避人类的能力免疫系统。
The malaria parasite Plasmodium falciparum has evolved an unusual genome structure. The majority of the genome is relatively stable, with mutation rates similar to most eukaryotic species. However, some regions are very unstable with high recombination rates, driving the generation of new immune evasion-associated var genes. The molecular factors controlling the inconsistent stability of this genome are not known. Here we studied the roles of the two putative RecQ helicases in P. falciparum, PfBLM and PfWRN. When PfWRN was knocked down, recombination rates increased four-fold, generating chromosomal abnormalities, a high rate of chimeric var genes and many microindels, particularly in known ‘fragile sites’. This is the first identification of a gene involved in suppressing recombination and maintaining genome stability in Plasmodium. By contrast, no change in mutation rate appeared when the second RecQ helicase, PfBLM, was mutated. At the transcriptional level, however, both helicases evidently modulate the transcription of large cohorts of genes, with several hundred genes—including a large proportion of vars—showing deregulated expression in each RecQ mutant. Aberrant processing of stalled replication forks is a possible mechanism underlying elevated mutation rates and this was assessed by measuring DNA replication dynamics in the RecQ mutant lines. Replication forks moved slowly and stalled at elevated rates in both mutants, confirming that RecQ helicases are required for efficient DNA replication. Overall, this work identifies the Plasmodium RecQ helicases as major players in DNA replication, antigenic diversification and genome stability in the most lethal human malaria parasite, with important implications for genome evolution in this pathogen. Human malaria is caused by Plasmodium parasites, with most of the mortality (almost half a million deaths each year) being caused by one species, Plasmodium falciparum. This parasite has an unusual genome: it is exceptionally biased towards A and T nucleotides rather than G and C, and it contains specific areas rich in hypervariable virulence-associated genes which evolve very rapidly to produce new variants. This evolution is probably vital for the parasite to evade the human immune system and maintain chronic infections, but how it is controlled at a molecular level remains unknown. We have identified a helicase in the parasite with a huge influence on genome stability and the rate of genome evolution. It appears to function by unwinding various unusual DNA structures, and if this fails then the genome becomes unstable. In addition, the transcription of many genes whose DNA tends to form secondary structures is affected, and DNA replication is impeded. If this helicase was expressed variably in different parasite strains infecting humans, it could influence the parasites’ ability to grow and replicate efficiently, and also, crucially, its ability to evolve and thus evade the human immune system.
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DOI：
10.1093/bioinformatics/btu638
发表时间：
2015-01-15
期刊：
Bioinformatics (Oxford, England)
影响因子：
--
作者：
Anders S;Pyl PT;Huber W
通讯作者：
Huber W
影响因子：
9.8
作者：
Bozdech, Zbynek;Llinas, Manuel;Pulliam, Brian Lee;Wong, Edith D;Zhu, Jingchun;DeRisi, Joseph L
通讯作者：
DeRisi, Joseph L
影响因子：
14.9
作者：
Deitsch, KW;Driskill, CL;Wellems, TE
通讯作者：
Wellems, TE
影响因子：
64.5
作者：
BARUCH, DI;PASLOSKE, BL;HOWARD, RJ
通讯作者：
HOWARD, RJ
影响因子：
15
作者：
Han, FXG;Wheelhouse, RT;Hurley, LH
通讯作者：
Hurley, LH