期刊
MOLECULAR CELL
卷 81, 期 22, 页码 4692-+出版社
CELL PRESS
DOI: 10.1016/j.molcel.2021.09.005
关键词
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资金
- European Union Horizon 2020 research and innovation program under the Marie Sklodowska-Curie grant [722729]
- Dutch Research Council [Vici 91814643, Vidi 193.131]
- Dutch Cancer Society (KWF) [11008]
- Oncode Institute
- Swiss National Science Foundation [310030_179360]
- Swiss Cancer League [KLS-4282-08-2017]
- Danish Cancer Society [R204-A12617-B153, R167-A11068]
- Danish Council for Independent Research [DFF-7016-00313]
- Novo Nordisk Foundation [16854, 0060590]
- Danish National Research Foundation [DNRF 125]
- LundbeckFonden [R322-2019-2577]
- Swedish Research Council [VR-MH 2014-46602-117891-30]
- Swedish Cancer Foundation [170176]
- [R01 CA254037]
A study reveals that loss of LIG3 enhances the toxicity of PARP inhibitors in BRCA1-deficient cancer, potentially serving as a therapeutic target.
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.
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