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首页> 外文期刊>Molecular Cancer >Replication stress induces specific enrichment of RECQ1 at common fragile sites FRA3B and FRA16D
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Replication stress induces specific enrichment of RECQ1 at common fragile sites FRA3B and FRA16D

机译：复制压力在常见的脆弱部位FRA3B和FRA16D诱导RECQ1的特异性富集

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Background Stalled replication forks at common fragile sites are a major cause of genomic instability. RecQ helicases, a highly conserved family of DNA-unwinding enzymes, are believed to ease ‘roadblocks’ that pose challenge to replication fork progression. Among the five known RecQ homologs in humans, functions of RECQ1, the most abundant of all, are poorly understood. We previously determined that RECQ1 helicase preferentially binds and unwinds substrates that mimic DNA replication/repair intermediates, and interacts with proteins involved in DNA replication restart mechanisms. Method We have utilized chromatin immunoprecipitation followed by quantitative real-time PCR to investigate chromatin interactions of RECQ1 at defined genetic loci in the presence or absence of replication stress. We have also tested the sensitivity of RECQ1-depleted cells to aphidicolin induced replication stress. Results RECQ1 binds to the origins of replication in unperturbed cells. We now show that conditions of replication stress induce increased accumulation of RECQ1 at the lamin B2 origin in HeLa cells. Consistent with a role in promoting fork recovery or repair, RECQ1 is specifically enriched at two major fragile sites FRA3B and FRA16D where replication forks have stalled following aphidicolin treatment. RECQ1-depletion results in attenuated checkpoint activation in response to replication stress, increased sensitivity to aphidicolin and chromosomal instability. Conclusions Given a recent biochemical observation that RECQ1 catalyzes strand exchange on stalled replication fork structures in vitro, our results indicate that RECQ1 facilitates repair of stalled or collapsed replication forks and preserves genome integrity. Our findings provide the first evidence of a crucial role for RECQ1 at naturally occurring fork stalling sites and implicate RECQ1 in mechanisms underlying common fragile site instability in cancer.
机译：背景技术在常见的易碎位点处停滞的复制叉是基因组不稳定的主要原因。 RecQ解旋酶是一种高度保守的DNA解旋酶家族，据信可以缓解“路障”，这对复制叉的发展提出了挑战。在人类已知的五个RecQ同源物中，对RECQ1的功能（最丰富的功能）了解得很少。我们先前确定RECQ1解旋酶优先结合和解旋模拟DNA复制/修复中间体的底物，并与涉及DNA复制重启机制的蛋白质相互作用。方法我们利用染色质免疫沉淀，然后进行定量实时PCR，研究在存在或不存在复制应激条件下，RECQ1在定义的基因位点的染色质相互作用。我们还测试了RECQ1耗尽的细胞对蚜虫素诱导的复制压力的敏感性。结果RECQ1绑定到不受干扰的细胞中的复制起点。现在，我们显示复制压力的条件在HeLa细胞的层粘连蛋白B2起点诱导RECQ1积累增加。 RECQ1具有促进叉修复或修复的作用，在两个主要的易碎部位FRA3B和FRA16D中特别富集，在这些部位上蚜虫菌素处理后复制叉停滞了。 RECQ1耗尽导致响应复制压力的检查点激活减弱，对蚜虫碱的敏感性增加和染色体不稳定。结论鉴于最近的生化观察，RECQ1在体外催化了停滞的复制叉结构上的链交换，我们的结果表明RECQ1促进了停滞或折叠的复制叉的修复并保留了基因组的完整性。我们的发现为RECQ1在自然发生的叉子失速位点发挥关键作用提供了第一个证据，并暗示RECQ1参与了癌症中常见的脆弱位点不稳定的潜在机制。

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