UBQLN1 deficiency mediates telomere shortening and IPF through interacting with RPA1.
UBQLN1 deficiency mediates telomere shortening and IPF through interacting with RPA1.
复制标题
DOI：
10.1371/journal.pgen.1010856
复制
发表时间：
2023-07
期刊：
影响因子：
4.5
通讯作者：
中科院分区：
文献类型：
--
作者：
端粒过早缩短是与特发性肺纤维化（IPF）发生相关的已知因素，IPF是一种慢性，进行性，与年龄相关的高死亡率疾病。IPF的病因尚不清楚。在这里，我们发现UBQLN1在端粒长度维持中起关键作用，并且可能与IPF有关。UBQLN1通过与RPA1相互作用并将其从复制叉上转移出去，从而参与DNA复制。UBQLN1缺乏使RPA1保留在复制叉上，阻碍复制，从而导致细胞周期阻滞和基因组不稳定。特别是在基因组的端粒区域，由于富含G的序列，存在更多的内源性复制应激，UBQLN1的缺失导致HeLa细胞端粒快速缩短。结果表明，UBQLN1缺失还会缩短小鼠肺端粒长度，加速小鼠肺纤维化。此外，UBQLN1在IPF患者中的表达水平下调，与预后不良相关。总之，这些结果揭示了UBQLN1在确保DNA复制和维持端粒稳定性方面的新作用，这可能有助于揭示IPF的发病机制和预防。特发性肺纤维化（IPF）是一种与年龄相关的疾病，病因不明，但与端粒长度有关。在这项研究中，我们发现UBQLN1通过将RPA1从复制叉上转移出去来调节端粒长度。UBQLN1缺乏导致复制问题和端粒缩短。更重要的是，敲低IPF小鼠肺细胞中的UBQLN1会加速肺衰老，加重肺纤维化。我们的工作表明UBQLN1在端粒维持和IPF发病机制中起重要作用。
Premature telomere shortening is a known factor correlated to idiopathic pulmonary fibrosis (IPF) occurrence, which is a chronic, progressive, age-related disease with high mortality. The etiology of IPF is still unknown. Here, we found that UBQLN1 plays a key role in telomere length maintenance and is potentially relevant to IPF. UBQLN1 involves in DNA replication by interacting with RPA1 and shuttling it off from the replication fork. The deficiency of UBQLN1 retains RPA1 at replication fork, hinders replication and thus causes cell cycle arrest and genome instability. Especially at telomere regions of the genome, where more endogenous replication stress exists because of G rich sequences, UBQLN1 depletion leads to rapid telomere shortening in HeLa cells. It revealed that UBQLN1 depletion also shortens telomere length at mouse lung and accelerates mouse lung fibrosis. In addition, the UBQLN1 expression level in IPF patients is downregulated and correlated to poor prognosis. Altogether, these results uncover a new role of UBQLN1 in ensuring DNA replication and maintaining telomere stability, which may shed light on IPF pathogenesis and prevention. Idiopathic pulmonary fibrosis (IPF) is an age-related disease with unknown etiology but correlated with telomere length. In this study, we discovered that UBQLN1 regulates the telomere length by shuttling the RPA1 off from replication fork. The deficiency of UBQLN1 causes replication problem and telomere shortening. More importantly, knockdown the UBQLN1 at IPF mice lung cells would accelerate lung senescence and aggravate lung fibrosis. Our work demonstrates that UBQLN1 plays an important role in telomere maintenance and IPF pathogenesis.
登录
查看更多内容
DOI：
10.1038/nrg3246
发表时间：
2012-10
期刊：
Nature reviews. Genetics
影响因子：
--
作者：
通讯作者：
--
影响因子：
4
作者：
Kurlawala Z;Shah PP;Shah C;Beverly LJ
通讯作者：
Beverly LJ
影响因子：
3.7
作者：
Martens, UM;Chavez, EA;Landsdorp, PM
通讯作者：
Landsdorp, PM
影响因子：
--
作者：
Abbas T;Dutta A
通讯作者：
Dutta A
影响因子：
8
作者：
McDonough, John E.;Ahangari, Farida;Kaminski, Naftali
通讯作者：
Kaminski, Naftali