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Cancer-associated mutations in the iron-sulfur domain of FANCJ affect G-quadruplex metabolism.

FANCJ 铁硫结构域的癌症相关突变影响 G-四链体代谢。

  • 影响因子:5.00
  • DOI:10.1371/journal.pgen.1008740
  • 作者列表:"Odermatt DC","Lee WTC","Wild S","Jozwiakowski SK","Rothenberg E","Gari K
  • 发表时间:2020-06-15
Abstract

:FANCJ/BRIP1 is an iron-sulfur (FeS) cluster-binding DNA helicase involved in DNA inter-strand cross-link (ICL) repair and G-quadruplex (G4) metabolism. Mutations in FANCJ are associated with Fanconi anemia and an increased risk for developing breast and ovarian cancer. Several cancer-associated mutations are located in the FeS domain of FANCJ, but how they affect FeS cluster binding and/or FANCJ activity has remained mostly unclear. Here we show that the FeS cluster is indispensable for FANCJ's ability to unwind DNA substrates in vitro and to provide cellular resistance to agents that induce ICLs. Moreover, we find that FANCJ requires an intact FeS cluster for its ability to unfold G4 structures on the DNA template in a primer extension assay with the lagging-strand DNA polymerase delta. Surprisingly, however, FANCJ variants that are unable to bind an FeS cluster and to unwind DNA in vitro can partially suppress the formation of replisome-associated G4 structures that we observe in a FANCJ knock-out cell line. This may suggest a partially retained cellular activity of FANCJ variants with alterations in the FeS domain. On the other hand, FANCJ knock-out cells expressing FeS cluster-deficient variants display a similar-enhanced-sensitivity towards pyridostatin (PDS) and CX-5461, two agents that stabilise G4 structures, as FANCJ knock-out cells. Mutations in FANCJ that abolish FeS cluster binding may hence be predictive of an increased cellular sensitivity towards G4-stabilising agents.

摘要

: FANCJ/BRIP1 是一种铁硫 (FeS) 簇结合 DNA 解旋酶,参与 DNA 链间交联 (ICL) 修复和 G-四链体 (G4) 代谢。FANCJ 的突变与范可尼贫血和患乳腺癌和卵巢癌的风险增加有关。几种癌症相关突变位于 FANCJ 的 FeS 结构域,但它们如何影响 FeS 簇结合和/或 FANCJ 活性仍不清楚。在这里,我们证明了 FeS 簇对于 FANCJ 在体外展开 DNA 底物的能力以及对诱导 ICLs 的药物提供细胞抗性的能力是不可或缺的。此外,我们发现 FANCJ 在用滞后链 DNA 聚合酶 δ 进行引物延伸试验时,需要一个完整的 FeS 簇,以便能够在 DNA 模板上展开 G4 结构。然而,令人惊讶的是,无法结合 FeS 簇并在体外展开 DNA 的 FANCJ 变异体可以部分抑制我们在 FANCJ 敲除细胞系中观察到的复制体相关 G4 结构的形成。这可能表明部分保留了 FANCJ 变异体的细胞活性,FeS 结构域发生了改变。另一方面,表达 FeS 簇缺陷变体的 FANCJ 基因敲除细胞对吡啶抑素 (PDS) 和 CX-5461 (两种稳定 G4 结构的药物) 表现出相似的增强敏感性,作为 FANCJ 基因敲除细胞。因此,取消 FeS 簇结合的 FANCJ 突变可能预示着细胞对 G4-stabilising 药物的敏感性增加。

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影响因子:3.18
发表时间:2020-01-29
来源期刊:Vaccine
DOI:10.1016/j.vaccine.2019.11.019
作者列表:["Shilling H","Murray G","Brotherton JML","Hawkes D","Saville M","Sivertsen T","Chambers I","Roberts J","Farnsworth A","Garland SM","Hocking JS","Kaldor J","Guy R","Atchison S","Costa AM","Molano M","Machalek DA"]

METHODS:INTRODUCTION:Australia has recently implemented major changes in cervical cancer prevention policies including introduction of primary human papillomavirus (HPV) screening starting at age 25, and replacement of the quadrivalent HPV vaccine with the nonavalent vaccine in the national school-based program. We assessed the feasibility and utility of conducting HPV testing in residual clinical specimens submitted for routine Chlamydia trachomatis screening, as a means of tracking HPV vaccine program impact among young sexually active women. METHODS:De-identified residual specimens from women aged 16-24 years submitted for chlamydia testing were collected from three pathology laboratories in Victoria and New South Wales. Limited demographic information, and chlamydia test results were also collected. Patient identifiers were sent directly from the laboratories to the National HPV Vaccination Program Register, to obtain HPV vaccination histories. Samples underwent HPV genotyping using Seegene Anyplex II HPV 28 assay. RESULTS:Between April and July 2018, 362 residual samples were collected, the majority (60.2%) of which were cervical swabs. Demographic data and vaccination histories were received for 357 (98.6%) women (mean age 21.8, SD 2.0). Overall, 65.6% of women were fully vaccinated, 9.8% partially, and 24.7% unvaccinated. The majority (86.0%) resided in a major city, 35.9% were classified in the upper quintile of socioeconomic advantage and chlamydia positivity was 7.8%.The prevalence of quadrivalent vaccine-targeted types (HPV6/11/16/18) was 2.8% (1.5-5.1%) overall with no differences by vaccination status (p = 0.729). The prevalence of additional nonavalent vaccine-targeted types (HPV31/33/45/52/58) was 19.3% (15.6-23.8%). One or more oncogenic HPV types were detected in 46.8% (95% CI 41.6-52.0%) of women. CONCLUSIONS:HPV testing of residual chlamydia specimens provides a simple, feasible method for monitoring circulating genotypes. Applied on a larger scale this method can be utilised to obtain a timely assessment of nonavalent vaccine impact among young women not yet eligible for cervical screening.

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影响因子:4.02
发表时间:2020-01-29
来源期刊:Journal of virology
DOI:10.1128/JVI.00090-20
作者列表:["Boon SS","Xia C","Lim JY","Chen Z","Law PTY","Yeung ACM","Thomas M","Banks L","Chan PKS"]

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