Loss of nuclear DNA ligase III reverts PARP inhibitor resistance in BRCA1/53BP1 double-deficient cells by exposing ssDNA gaps

Mariana Paes Dias, Vivek Tripathi, Ingrid van der Heijden, Ke Cong, Eleni Maria Manolika, Jinhyuk Bhin, Ewa Gogola, Panagiotis Galanos, Stefano Annunziato, Cor Lieftink, Miguel Andújar-Sánchez, Sanjiban Chakrabarty, Graeme C.M. Smith, Marieke van de Ven, Roderick L. Beijersbergen, Jirina Bartkova, Sven Rottenberg, Sharon Cantor, Jiri Bartek, Arnab Ray Chaudhuri*Jos Jonkers*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

5 Citations (Scopus)

Abstract

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 languageEnglish
Pages (from-to)4692-4708.e9
JournalMolecular Cell
Volume81
Issue number22
DOIs
Publication statusPublished - 18 Nov 2021

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