PT  - JOURNAL ARTICLE
AU  - Mariana Paes Dias
AU  - Vivek Tripathi
AU  - Ingrid van der Heijden
AU  - Ke Cong
AU  - Eleni-Maria Manolika
AU  - Jinhyuk Bhin
AU  - Ewa Gogola
AU  - Panagiotis Galanos
AU  - Stefano Annunziato
AU  - Cor Lieftink
AU  - Miguel Andújar-Sánchez
AU  - Sanjiban Chakrabarty
AU  - Graeme C. M. Smith
AU  - Marieke van de Ven
AU  - Roderick L. Beijersbergen
AU  - Jirina Bartkova
AU  - Sven Rottenberg
AU  - Sharon Cantor
AU  - Jiri Bartek
AU  - Arnab Ray Chaudhuri
AU  - Jos Jonkers
TI  - Loss of Nuclear DNA Ligase III Reverts PARP Inhibitor Resistance in BRCA1/53BP1 Double-deficient Cells by Exposing ssDNA Gaps
AID  - 10.1101/2021.03.24.436323
DP  - 2021 Jan 01
TA  - bioRxiv
PG  - 2021.03.24.436323
4099  - http://biorxiv.org/content/early/2021/07/20/2021.03.24.436323.short
4100  - http://biorxiv.org/content/early/2021/07/20/2021.03.24.436323.full
AB  - 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.Competing Interest StatementG.C.M.S is an employee and shareholder of ArtiosPharma Ltd and of AstraZeneca PLC. All other authors declare no potential conflicts of interest.