RT Journal Article SR Electronic T1 Loss of Nuclear DNA ligase III Can Revert PARP Inhibitor Resistance in BRCA1-deficient Cells by Increasing DNA Replication Stress JF bioRxiv FD Cold Spring Harbor Laboratory SP 2021.03.24.436323 DO 10.1101/2021.03.24.436323 A1 Mariana Paes Dias A1 Vivek Tripathi A1 Ingrid van der Heijden A1 Ke Cong A1 Eleni-Maria Manolika A1 Panagiotis Galanos A1 Jinhyuk Bhin A1 Ewa Gogola A1 Stefano Annunziato A1 Cor Lieftink A1 Miguel Andújar-Sánchez A1 Marieke van de Ven A1 Sanjiban Chakrabarty A1 Roderick L. Beijersbergen A1 Jirina Bartkova A1 Sven Rottenberg A1 Sharon Cantor A1 Jiri Bartek A1 Arnab Ray Chaudhuri A1 Jos Jonkers YR 2021 UL http://biorxiv.org/content/early/2021/03/24/2021.03.24.436323.abstract 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 is required for PARPi-induced fork acceleration in BRCA1-deficient cells and that LIG3 loss increases fork asymmetry. Furthermore, LIG3 depletion in BRCA1-deficient cells results in an increase in ssDNA gaps behind the replication forks, resulting in accumulation of chromosomal abnormalities. We also report that high expression of LIG3 in patients with invasive breast cancer correlates in with poorer overall survival, rendering LIG3 as a potential therapeutic target for enhancing PARPi sensitivity.Competing Interest StatementThe authors have declared no competing interest.