Provencher Luc, Nartey Wilson, Brownlee Peter M, Atkins Austin W, Gagné Jean-Philippe, Baudrier Lou, Ting Nicholas S Y, Piett Cortt G, Fang Shujuan, Pearson Dustin D, Moore Shaun, Billon Pierre, Nagel Zachary D, Poirier Guy G, Williams Gareth J, Goodarzi Aaron A
Robson DNA Science Centre, Charbonneau Cancer Institute, Department of Biochemistry & Molecular Biology, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada.
Department of Molecular Biology, Medical Biochemistry and Pathology, Laval University Cancer Research Center, Quebec City, QC, Canada.
Nat Commun. 2025 Jan 25;16(1):1026. doi: 10.1038/s41467-025-56085-5.
To tolerate oxidative stress, cells enable DNA repair responses often sensitive to poly(ADP-ribose) (PAR) polymerase 1 and 2 (PARP1/2) inhibition-an intervention effective against cancers lacking BRCA1/2. Here, we demonstrate that mutating the CHD6 chromatin remodeler sensitizes cells to PARP1/2 inhibitors in a manner distinct from BRCA1, and that CHD6 recruitment to DNA damage requires cooperation between PAR- and DNA-binding domains essential for nucleosome sliding activity. CHD6 displays direct PAR-binding, interacts with PARP-1 and other PAR-associated proteins, and combined DNA- and PAR-binding loss eliminates CHD6 relocalization to DNA damage. While CHD6 loss does not impair RAD51 foci formation or DNA double-strand break repair, it causes sensitivity to replication stress, and PARP1/2-trapping or Pol ζ inhibitor-induced γH2AX foci accumulation in S-phase. DNA repair pathway screening reveals that CHD6 loss elicits insufficiency in apurinic-apyrimidinic endonuclease (APEX1) activity and genomic abasic site accumulation. We reveal APEX1-linked roles for CHD6 important for understanding PARP1/2-trapping inhibitor sensitivity.
为了耐受氧化应激，细胞会启动通常对聚（ADP - 核糖）（PAR）聚合酶1和2（PARP1/2）抑制敏感的DNA修复反应——这种干预对缺乏BRCA1/2的癌症有效。在这里，我们证明，突变CHD6染色质重塑因子会以一种不同于BRCA1的方式使细胞对PARP1/2抑制剂敏感，并且CHD6募集到DNA损伤位点需要PAR结合域和DNA结合域之间的协同作用，这对于核小体滑动活性至关重要。CHD6表现出直接的PAR结合能力，与PARP - 1和其他PAR相关蛋白相互作用，并且DNA结合和PAR结合功能的丧失共同消除了CHD6重新定位到DNA损伤位点的能力。虽然CHD6的缺失不会损害RAD51焦点的形成或DNA双链断裂修复，但它会导致细胞对复制应激敏感，以及在S期出现PARP1/2捕获或Pol ζ抑制剂诱导的γH2AX焦点积累。DNA修复途径筛选显示，CHD6的缺失会导致无嘌呤 - 无嘧啶内切酶（APEX1）活性不足和基因组无碱基位点积累。我们揭示了CHD6与APEX1相关的作用，这对于理解PARP1/2捕获抑制剂敏感性很重要。
