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

Paes Dias, Mariana; Tripathi, Vivek; van der Heijden, Ingrid; Cong, Ke; Manolika, Eleni-Maria; Bhin, Jinhyuk; Gogola, Ewa; Galanos, Panagiotis; Annunziato, Stefano; Lieftink, Cor; Andújar-Sánchez, Miguel; Chakrabarty, Synjiban; Smith, Graeme C. M.; van de Ven, Marieke; Beijersbergen, Roderick; Bartkova, Jirina; Rottenberg, Sven; Cantor, Sharon; Bartek, Jiri; Chaudhuri, Arnab Ray; ... (2021). Loss of nuclear DNA ligase III reverts PARP inhibitor resistance in BRCA1/53BP1 double-deficient cells by exposing ssDNA gaps. Molecular cell, 81(22), pp. 4692-4708. Cell Press 10.1016/j.molcel.2021.09.005

Preview	Text COMBINED_MS_LIG3_20_7_21.pdf - Accepted Version Available under License Creative Commons: Attribution-Noncommercial-No Derivative Works (CC-BY-NC-ND). Download (13MB) | Preview
	Text 1-s2.0-S1097276521007395-main.pdf - Published Version Restricted to registered users only Available under License Publisher holds Copyright. Download (4MB)

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.

Interest & Impact

Downloads

116 since deposited on 23 Feb 2022
61 in the past 12 months

Citations

5 Citations in Web of Science ®
6 Citations in Scopus

Search

in Google Scholar™

Services

Actions (login required)

Edit item

Actions (login required)

Edit item