A new pathway that regulates 53BP1 stability implicates Cathepsin L and vitamin D in DNA repair
A new pathway that regulates 53BP1 stability implicates Cathepsin L and vitamin D in DNA repair
复制标题
DOI：
10.1038/emboj.2011.225
复制
发表时间：
2011-08-17
期刊：
影响因子：
11.4
通讯作者：
Gonzalo, Susana
中科院分区：
文献类型：
--
作者：
Gonzalez-Suarez, Ignacio;Redwood, Abena B.;Gonzalo, Susana
端粒功能障碍和 DNA 双链断裂 (DSB) 修复缺陷导致的基因组不稳定是衰老相关疾病的根本原因。 53BP1 是 DNA DSB 修复的关键因素，其缺陷与基因组不稳定和癌症进展相关。在这里，我们发现了一条调节 53BP1 稳定性的新途径。我们证明了半胱氨酸蛋白酶组织蛋白酶 L (CTSL) 在 53BP1 降解中发挥着前所未有的作用。 CTSL 在野生型成纤维细胞中过度表达会导致 53BP1 蛋白水平降低及其细胞分布发生变化，从而导致 DNA DSB 修复缺陷。重要的是，我们表明，A 型核纤层蛋白丢失后与 53BP1 缺陷相关的 DNA 修复缺陷是由于 CTSL 的上调所致。此外，我们证明维生素 D 治疗可以稳定 53BP1，并通过抑制 CTSL 促进 DNA DSB 修复，从而在维生素 D 作用和 DNA 修复之间提供了迄今为止未被怀疑的联系。鉴于 CTSL 上调是癌症和早衰症的标志，调节该通路可能对这些疾病具有重要的治疗意义。 EMBO 杂志 (2011) 30, 3383-3396。 doi：10.1038/emboj.2011.225； 2011 年 7 月 12 日在线发布
Genomic instability due to telomere dysfunction and defective repair of DNA double-strand breaks (DSBs) is an underlying cause of ageing-related diseases. 53BP1 is a key factor in DNA DSBs repair and its deficiency is associated with genomic instability and cancer progression. Here, we uncover a novel pathway regulating the stability of 53BP1. We demonstrate an unprecedented role for the cysteine protease Cathepsin L (CTSL) in the degradation of 53BP1. Overexpression of CTSL in wild-type fibroblasts leads to decreased 53BP1 protein levels and changes in its cellular distribution, resulting in defective repair of DNA DSBs. Importantly, we show that the defects in DNA repair associated with 53BP1 deficiency upon loss of A-type lamins are due to upregulation of CTSL. Furthermore, we demonstrate that treatment with vitamin D stabilizes 53BP1 and promotes DNA DSBs repair via inhibition of CTSL, providing an as yet unsuspected link between vitamin D action and DNA repair. Given that CTSL upregulation is a hallmark of cancer and progeria, regulation of this pathway could be of great therapeutic significance for these diseases. The EMBO Journal (2011) 30, 3383-3396. doi:10.1038/emboj.2011.225; Published online 12 July 2011