Lamin A/C recruits ssDNA protective proteins RPA and RAD51 to stalled replication forks to maintain fork stability.
Lamin A/C recruits ssDNA protective proteins RPA and RAD51 to stalled replication forks to maintain fork stability.
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DOI：
10.1016/j.jbc.2021.101301
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发表时间：
2021-11
期刊：
影响因子：
--
通讯作者：
Gonzalo S
中科院分区：
文献类型：
--
作者：
Graziano S;Coll-Bonfill N;Teodoro-Castro B;Kuppa S;Jackson J;Shashkova E;Mahajan U;Vindigni A;Antony E;Gonzalo S
核纤层蛋白A/C为基因组功能的区室化提供了核支架，这对基因组完整性很重要。核纤层蛋白A/C功能障碍与癌症、衰老和退行性疾病有关。核纤层蛋白A/C调节基因组稳定性的机制仍然知之甚少。我们证明了核纤层蛋白A/C在DNA复制中的关键作用。核纤层蛋白A/C与新生DNA结合，特别是在复制应激（RS）期间，确保复制叉保护因子RPA和RAD 51的募集。这些ssDNA结合蛋白分别被认为是RS的第一和第二应答者，在稳定、重塑和修复停滞的分叉中发挥作用，以确保正确的重启和基因组稳定性。核纤层蛋白A/C缺失后RPA和RAD 51的募集减少导致复制叉不稳定性（RFI），其特征为MRE 11核酸酶介导的新生DNA降解、RS诱导的DNA损伤和对复制抑制剂的敏感性。重要的是，与同源重组缺陷细胞不同，核纤层蛋白A/C缺失细胞中的RFI与复制叉逆转无关。因此，核酸酶的进入点不是反向叉，而是在RS期间产生的ssDNA的不受RPA和RAD 51保护的区域。一致地，核纤层蛋白A/C耗尽的细胞中的RFI通过RPA或RAD 51的外源性过表达来拯救。这些数据揭示了结构核蛋白参与RS期间通过促进RPA和RAD 51向停滞叉的募集来保护ssDNA免受核酸酶的影响。支持这一模型，我们显示RPA和核纤层蛋白A/C之间的物理相互作用。我们认为RS是核纤层蛋白病和核纤层蛋白A/C缺陷型肿瘤中基因组不稳定的主要来源。
Lamin A/C provides a nuclear scaffold for compartmentalization of genome function that is important for genome integrity. Lamin A/C dysfunction is associated with cancer, aging, and degenerative diseases. The mechanisms whereby lamin A/C regulates genome stability remain poorly understood. We demonstrate a crucial role for lamin A/C in DNA replication. Lamin A/C binds to nascent DNA, especially during replication stress (RS), ensuring the recruitment of replication fork protective factors RPA and RAD51. These ssDNA-binding proteins, considered the first and second responders to RS respectively, function in the stabilization, remodeling, and repair of the stalled fork to ensure proper restart and genome stability. Reduced recruitment of RPA and RAD51 upon lamin A/C depletion elicits replication fork instability (RFI) characterized by MRE11 nuclease–mediated degradation of nascent DNA, RS-induced DNA damage, and sensitivity to replication inhibitors. Importantly, unlike homologous recombination–deficient cells, RFI in lamin A/C-depleted cells is not linked to replication fork reversal. Thus, the point of entry of nucleases is not the reversed fork but regions of ssDNA generated during RS that are not protected by RPA and RAD51. Consistently, RFI in lamin A/C-depleted cells is rescued by exogenous overexpression of RPA or RAD51. These data unveil involvement of structural nuclear proteins in the protection of ssDNA from nucleases during RS by promoting recruitment of RPA and RAD51 to stalled forks. Supporting this model, we show physical interaction between RPA and lamin A/C. We suggest that RS is a major source of genomic instability in laminopathies and lamin A/C-deficient tumors.
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影响因子：
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作者：
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