Senataxin plays an essential role with DNA damage response proteins in meiotic recombination and gene silencing.
Senataxin plays an essential role with DNA damage response proteins in meiotic recombination and gene silencing.
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DOI：
10.1371/journal.pgen.1003435
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发表时间：
2013-04
期刊：
影响因子：
4.5
通讯作者：
Lavin MF
中科院分区：
文献类型：
--
作者：
Becherel OJ;Yeo AJ;Stellati A;Heng EY;Luff J;Suraweera AM;Woods R;Fleming J;Carrie D;McKinney K;Xu X;Deng C;Lavin MF
Senataxin在人类遗传性疾病共济失调伴眼用不能2型（AOA2）中突变，通过协调转录、DNA复制和DNA损伤反应在维持基因组完整性方面发挥重要作用。我们表明，senataxin是必不可少的精子发生，它的功能在两个阶段在减数分裂过程中的交叉在同源重组和减数分裂性染色体失活（MSCI）。Setx基因的破坏导致DNA双链断裂的持续存在，Rad51细丝解体的缺陷，DNA：RNA杂合体（R环）的积累，以及最终的交换失败。Senataxin以Brca1依赖的方式定位于XY体，在其不存在的情况下，DNA损伤反应蛋白不完全定位于XY染色体，ATR保留在这些染色体的轴向元件上，未能扩散到染色质中。此外，RNA聚合酶II活性的持续存在、ubH2A分布的改变以及Setx −/−中XY连锁基因表达的异常揭示了Senataxin在MSCI中的重要作用。这些数据支持senataxin在协调减数分裂交换与转录以及基因沉默以保护基因组完整性方面的关键作用。由Setx基因（编码senataxin）缺陷引起的共济失调伴眼动性失用2型（AOA 2）是常染色体隐性共济失调亚组的一部分，其特征是负责识别和/或修复DNA损伤的基因缺陷。来自这些患者的细胞的特征在于氧化应激，并且在RNA加工和转录终止方面有缺陷。最近的数据表明，senataxin参与协调DNA复制叉和正在进行的转录之间的事件。为了进一步了解senataxin的作用，我们破坏了小鼠的Setx基因，并证明了其在减数分裂重组和减数分裂性染色体失活（MSCI）过程中在精子发生中的重要作用。在没有senataxin的情况下，DNA双链断裂持续存在，RNA：DNA杂合体（R环）积累，同源重组被破坏。Senataxin在粗线期定位于XY染色体。这依赖于Brca1，它在MSCI早期起作用，将DNA损伤反应蛋白招募到XY体。在没有senataxin的情况下，DNA损伤反应蛋白在XY染色体上的积累不完全，ATR没有MDC1依赖性扩散到更广泛的XY染色质。最终结果是MSCI缺陷、细胞凋亡和减数分裂失败。
Senataxin, mutated in the human genetic disorder ataxia with oculomotor apraxia type 2 (AOA2), plays an important role in maintaining genome integrity by coordination of transcription, DNA replication, and the DNA damage response. We demonstrate that senataxin is essential for spermatogenesis and that it functions at two stages in meiosis during crossing-over in homologous recombination and in meiotic sex chromosome inactivation (MSCI). Disruption of the Setx gene caused persistence of DNA double-strand breaks, a defect in disassembly of Rad51 filaments, accumulation of DNA:RNA hybrids (R-loops), and ultimately a failure of crossing-over. Senataxin localised to the XY body in a Brca1-dependent manner, and in its absence there was incomplete localisation of DNA damage response proteins to the XY chromosomes and ATR was retained on the axial elements of these chromosomes, failing to diffuse out into chromatin. Furthermore persistence of RNA polymerase II activity, altered ubH2A distribution, and abnormal XY-linked gene expression in Setx−/− revealed an essential role for senataxin in MSCI. These data support key roles for senataxin in coordinating meiotic crossing-over with transcription and in gene silencing to protect the integrity of the genome. Ataxia with oculomotor apraxia type 2 (AOA2) caused by a defect in the gene Setx (coding for senataxin) is part of a subgroup of autosomal recessive ataxias characterized by defects in genes responsible for the recognition and/or repair of damage in DNA. Cells from these patients are characterized by oxidative stress and are defective in RNA processing and termination of transcription. Recent data suggest that senataxin is involved in coordinating events between DNA replication forks and ongoing transcription. To further understand the role of senataxin, we disrupted the Setx gene in mice and demonstrated its essential role in spermatogenesis during meiotic recombination and in meiotic sex chromosome inactivation (MSCI). In the absence of senataxin, DNA double-strand breaks persist, RNA:DNA hybrids (R-loops) accumulate, and homologous recombination is disrupted. Senataxin localised to the XY chromosomes during pachytene. This was dependent on Brca1, which functions early in MSCI to recruit DNA damage response proteins to the XY body. In the absence of senataxin, there was incomplete accumulation of DNA damage response proteins on the XY chromosomes and no MDC1-dependent diffusion of ATR to the broader XY chromatin. The end result was a defect in MSCI, apoptosis, and a failure to complete meiosis.
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