膀胱癌是全球十大常見癌症之一。以鉑類為基礎的輔助化療是肌層浸潤性膀胱癌（MIBC）患者的第一線治療方法。不幸的是，順鉑抗藥性是影響治療效果的主要障礙。因此，了解順鉑抗藥性的機制非常重要，這可以幫助我們找到對抗癌症的治療策略。基因組不穩定性是癌症的標誌之一。腫瘤發生的主要驅動因素之一是複製壓力引起的DNA雙股斷裂，導致大規模的染色體重組和基因體不穩定性。幾項研究已經揭示，複製叉保護有助於基因組穩定性和化療抗藥性。在本篇研究中，我們發現了APLF在交聯DNA修復和複製叉保護中的新功能。我們發現PARP1活性促進APLF的招募，有助於FANCD2招募至停滯的複製叉，並維持複製叉的穩定性。APLF的缺失或APLF的PBZ區域突變會藉由減少FANCD2招募至停滯複製叉影響複製叉保護，同時對順鉑變得敏感。我們進一步發現，順鉑抗藥物的癌細胞中APLF和同源重組相關基因的表現量高。我們的結果揭示了APLF在促進ICL修復和複製叉保護中的新功能，從而有助於癌細胞的順鉑抗藥性表型。

Bladder cancer is one of the top ten most common cancer types worldwide. Platinum-based neoadjuvant chemotherapy is a first-line treatment for muscle-invasive bladder cancer (MIBC) patients. Unfortunately, cisplatin resistance is the major obstacle for the efficacy of the treatment. Therefore, understanding the underlying mechanism of cisplatin resistance is important, which can lead us to find therapeutic strategy to combat cancers. Genomic instability is hallmarks of cancers. One of the major driver of tumorigenesis is replication stress-induced DNA double-strand breaks (DSBs), resulting in gross chromosomal rearrangements and genomic instability. Several studies have revealed that replication forks protection contributes to genome stability and chemoresistance. In this study, we identify a novel function of APLF involved in interstrand DNA crosslink (ICL) repair and fork protection. We found that PARP1 activity promotes APLF recruitment, which facilitates FANCD2 recruitment to stalled forks and maintain replication fork stability. The APLF-depletion or mutations in the PBZ-domain of APLF disrupts fork protection by reducing the FANCD2 recruitment to stalled forks, simultaneously being sensitive to cisplatin. We further identified that cisplatin-resistant cancer cells have high levels of APLF and homologous recombination-related gene expression. Our results reveale the novel function of APLF, which facilitates ICL repair and fork protection, thereby contributing to cisplatin-resistant phenotypes of cancer cells.

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