【文献速览】-ALC1 links chromatin acce

The response to poly(ADP-ribose) polymerase inhibitors (PARPi) is dictated by homologous recombination (HR) DNA repair and the abundance of lesions that trap PARP enzymes. It remains unclear, however, if the established role of PARP in promoting chromatin accessibility impacts viability in these settings. Using a CRISPR-based screen, we identified the PAR-binding chromatin remodeller ALC1/CHD1L as a key determinant of PARPi toxicity in HR-deficient cells. ALC1 loss reduced viability of breast cancer gene (BRCA)-mutant cells and enhanced sensitivity to PARPi by up to 250-fold, while overcoming several resistance mechanisms. ALC1 deficiency reduced chromatin accessibility concomitant with a decrease in the association of base damage repair factors. This resulted in an accumulation of replication-associated DNA damage, increased PARP trapping and a reliance on HR. These findings establish PAR-dependent chromatin remodelling as a mechanistically distinct aspect of PARPi responses and therapeutic target in HR-deficient cancers.
对聚(adp -核糖)聚合酶抑制剂(PARPi)的反应是由同源重组(HR) DNA修复和捕获PARP酶的大量病变决定的。然而，尚不清楚PARP在促进染色质可及性方面的既定作用是否会影响这些环境下的生存能力。通过基于crispr的筛选，我们发现par结合的染色质重塑剂ALC1/CHD1L是hr缺陷细胞中PARPi毒性的关键决定因素。ALC1缺失降低了乳腺癌基因(BRCA)突变细胞的生存能力，提高了对PARPi的敏感性高达250倍，同时克服了几种耐药性机制。ALC1缺乏降低了染色质可及性，同时降低了碱基损伤修复因子的相关性。这导致复制相关的DNA损伤的积累，增加PARP捕获和对HR的依赖。这些发现表明，在hr缺乏的癌症中，依赖par的染色质重塑是PARPi反应和治疗靶点的一个机制上不同的方面。