Two familial ALS proteins function in prevention/repair of transcription-associated DNA damage
Two familial ALS proteins function in prevention/repair of transcription-associated DNA damage
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DOI：
10.1073/pnas.1611673113
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发表时间：
2016-11-29
影响因子：
11.1
通讯作者：
Livingston, David M.
中科院分区：
文献类型：
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作者：
Hill, Sarah J.;Mordes, Daniel A.;Livingston, David M.
肌萎缩侧索硬化症（ALS）是一种进行性运动神经元功能障碍疾病，可导致瘫痪和死亡。目前还没有确定的分子发病机制途径。参与RNA加工的多种蛋白质与ALS相关，包括FUS和TDP 43，我们提出了一种疾病机制，其中至少一种蛋白质的功能丧失导致转录相关DNA损伤的积累，从而导致运动神经元细胞死亡和进行性神经症状。为了支持这一假设，我们发现FUS或TDP 43缺失导致对转录抑制剂的敏感性增加，这是由于DNA损伤增加。因此，这些蛋白质通常有助于预防或修复转录相关的DNA损伤。此外，FUS和TDP 43与活性RNA聚合酶II共定位于DNA损伤位点，沿着DNA损伤修复蛋白BRCA 1，并且FUS和TDP 43参与预防或修复R环相关的DNA损伤，这是异常转录和/或RNA加工的表现。更好地理解FUS和TDP 43在转录相关DNA损伤中的作用可以揭示ALS发病机制的潜在机制。
Amyotrophic lateral sclerosis (ALS) is a progressive motor neuron dysfunction disease that leads to paralysis and death. There is currently no established molecular pathogenesis pathway. Multiple proteins involved in RNA processing are linked to ALS, including FUS and TDP43, and we propose a disease mechanism in which loss of function of at least one of these proteins leads to an accumulation of transcription-associated DNA damage contributing to motor neuron cell death and progressive neurological symptoms. In support of this hypothesis, we find that FUS or TDP43 depletion leads to increased sensitivity to a transcription-arresting agent due to increased DNA damage. Thus, these proteins normally contribute to the prevention or repair of transcription-associated DNA damage. In addition, both FUS and TDP43 colocalize with active RNA polymerase II at sites of DNA damage along with the DNA damage repair protein, BRCA1, and FUS and TDP43 participate in the prevention or repair of R loop-associated DNA damage, a manifestation of aberrant transcription and/or RNA processing. Gaining a better understanding of the role(s) that FUS and TDP43 play in transcription-associated DNA damage could shed light on the mechanisms underlying ALS pathogenesis.