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染色质重塑因子 ALC1 是 PARP 抑制剂治疗耐药的基础。

The chromatin remodeler ALC1 underlies resistance to PARP inhibitor treatment.

机构信息

MTA SZBK Lendület DNA Damage and Nuclear Dynamics Research Group, Institute of Genetics, Biological Research Centre, 6276 Szeged, Hungary.

Univ Rennes, CNRS, IGDR (Institut de Génétique et Développement de Rennes), UMR 6290, BIOSIT, UMS 3480, F-35000 Rennes, France.

出版信息

Sci Adv. 2020 Dec 18;6(51). doi: 10.1126/sciadv.abb8626. Print 2020 Dec.

DOI:10.1126/sciadv.abb8626
PMID:33355125
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11206534/
Abstract

Poly(ADP-ribose) polymerase (PARP) inhibitors are used in the treatment of BRCA-deficient cancers, with treatments currently extending toward other homologous recombination defective tumors. In a genome-wide CRISPR knockout screen with olaparib, we identify ALC1 (Amplified in Liver Cancer 1)-a cancer-relevant poly(ADP-ribose)-regulated chromatin remodeling enzyme-as a key modulator of sensitivity to PARP inhibitor. We found that ALC1 can remove inactive PARP1 indirectly through binding to PARylated chromatin. Consequently, ALC1 deficiency enhances trapping of inhibited PARP1, which then impairs the binding of both nonhomologous end-joining and homologous recombination repair factors to DNA lesions. We also establish that ALC1 overexpression, a common feature in multiple tumor types, reduces the sensitivity of BRCA-deficient cells to PARP inhibitors. Together, we conclude that ALC1-dependent PARP1 mobilization is a key step underlying PARP inhibitor resistance.

摘要

聚（ADP-核糖）聚合酶（PARP）抑制剂被用于治疗 BRCA 缺陷型癌症，目前的治疗方法正在扩展到其他同源重组缺陷肿瘤。在使用奥拉帕利的全基因组 CRISPR 敲除筛选中，我们鉴定出 ALC1（肝癌扩增 1）-一种与癌症相关的聚（ADP-核糖）调节染色质重塑酶-是对 PARP 抑制剂敏感性的关键调节剂。我们发现，ALC1 可以通过与 PAR 化染色质结合，间接地去除失活的 PARP1。因此，ALC1 缺陷增强了抑制的 PARP1 的捕获，从而损害了非同源末端连接和同源重组修复因子与 DNA 损伤的结合。我们还确定，ALC1 的过表达是多种肿瘤类型的共同特征，降低了 BRCA 缺陷细胞对 PARP 抑制剂的敏感性。总之，我们的结论是，ALC1 依赖性 PARP1 动员是 PARP 抑制剂耐药性的关键步骤。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ff5b/11206534/7f9869432cae/abb8626-f6.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ff5b/11206534/7f9869432cae/abb8626-f6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ff5b/11206534/4f0d656500b5/abb8626-f1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ff5b/11206534/c64941323349/abb8626-f2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ff5b/11206534/d4ef1b5c73d9/abb8626-f3.jpg
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