Loss of nuclear DNA ligase III reverts PARP inhibitor resistance in BRCA1/53BP1 double-deficient cells by exposing ssDNA gaps.
Loss of nuclear DNA ligase III reverts PARP inhibitor resistance in BRCA1/53BP1 double-deficient cells by exposing ssDNA gaps.
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通过暴露ssDNA缺口，核DNA连接酶III的缺失恢复BRCA1/53BP1双缺陷细胞中PARP抑制剂的抗性。
DOI：
10.1016/j.molcel.2021.09.005
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发表时间：
2021-11-18
期刊：
影响因子：
16
通讯作者：
Jonkers, Jos
中科院分区：
文献类型：
--
作者：
Dias, Mariana Paes;Tripathi, Vivek;van der Heijden, Ingrid;Cong, Ke;Manolika, Eleni-Maria;Bhin, Jinhyuk;Gogola, Ewa;Galanos, Panagiotis;Annunziato, Stefano;Lieftink, Cor;Andujar-Sanchez, Miguel;Chakrabarty, Sanjiban;Smith, Graeme C. M.;van de Ven, Marieke;Beijersbergen, Roderick L.;Bartkova, Jirina;Rottenberg, Sven;Cantor, Sharon;Bartek, Jiri;Chaudhuri, Arnab Ray;Jonkers, Jos
聚（adp -核糖）（PAR）聚合酶（PARPi）抑制剂已进入临床治疗同源重组（HR）缺陷癌症。尽管这种方法取得了成功，但PARPi的临床前和临床研究已经揭示了多种耐药机制，强调了鉴定新的功能性生物标志物和联合治疗策略的必要性。在通过丢失53BP1获得PARPi抗性的细胞和类器官中进行的功能性遗传筛选发现，在brca1缺陷细胞中，LIG3的丢失是PARPi毒性的增强因子。LIG3缺失对PARPi毒性的增强依赖于BRCA1缺失，但与53BP1通路的缺失无关。在机制上，我们发现在暴露于PARPi的brca1缺陷和BRCA1/53BP1双缺陷细胞中，LIG3缺失促进mre11介导的复制后ssDNA缺口的形成，导致染色体异常的积累。LIG3缺失也增强了PARPi对小鼠brca1缺陷乳腺肿瘤的疗效，提示LIG3是一个潜在的治疗靶点。Paes Dias等报道，核LIG3的缺失通过促进mre11介导的复制后ssDNA间隙的形成，导致染色体异常的积累，从而增加了BRCA1/53BP1双缺陷细胞中PARPi的毒性。LIG3缺失也增强了PARPi对小鼠brca1缺陷乳腺肿瘤的疗效，提示LIG3是一个潜在的治疗靶点。
Inhibitors of poly(ADP-ribose) (PAR) polymerase (PARPi) have entered the clinic for the treatment of homologous recombination (HR)-deficient cancers. Despite the success of this approach, preclinical and clinical research with PARPi has revealed multiple resistance mechanisms, highlighting the need for identification of novel functional biomarkers and combination treatment strategies. Functional genetic screens performed in cells and organoids that acquired resistance to PARPi by loss of 53BP1 identified loss of LIG3 as an enhancer of PARPi toxicity in BRCA1-deficient cells. Enhancement of PARPi toxicity by LIG3 depletion is dependent on BRCA1 deficiency but independent of the loss of 53BP1 pathway. Mechanistically, we show that LIG3 loss promotes formation of MRE11-mediated post-replicative ssDNA gaps in BRCA1-deficient and BRCA1/53BP1 double-deficient cells exposed to PARPi, leading to an accumulation of chromosomal abnormalities. LIG3 depletion also enhances efficacy of PARPi against BRCA1-deficient mammary tumors in mice, suggesting LIG3 as a potential therapeutic target. Paes Dias et al. report that loss of nuclear LIG3 increases PARPi toxicity in BRCA1/53BP1 double-deficient cells by promoting the formation of MRE11-mediated post-replicative ssDNA gaps, leading to accumulation of chromosomal abnormalities. LIG3 depletion also enhances the efficacy of PARPi against BRCA1-deficient mammary tumors in mice, suggesting LIG3 as a potential therapeutic target.
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影响因子：
14.9
作者：
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通讯作者：
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影响因子：
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影响因子：
3.8
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影响因子：
48
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Rottenberg, Sven