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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.

Original publication

DOI

10.1016/j.molcel.2021.09.005

Type

Journal article

Journal

Molecular cell

Publication Date

11/2021

Volume

81

Pages

4692 - 4708.e9

Addresses

Division of Molecular Pathology, the Netherlands Cancer Institute, 1066CX Amsterdam, the Netherlands; Oncode Institute, 1066CX Amsterdam, the Netherlands.

Keywords

Cell Line, Cell Nucleus, Animals, Humans, Mice, Lentivirus, Ovarian Neoplasms, Mammary Neoplasms, Animal, DNA Damage, Chromosome Aberrations, BRCA1 Protein, RNA, Small Interfering, DNA, Single-Stranded, Biopsy, Cell Proliferation, Mutation, Transgenes, Female, Triple Negative Breast Neoplasms, CRISPR-Cas Systems, Poly(ADP-ribose) Polymerase Inhibitors, DNA Ligase ATP, Tumor Suppressor p53-Binding Protein 1, Poly-ADP-Ribose Binding Proteins, MRE11 Homologue Protein