AKT inhibition impairs PCNA ubiquitylation and triggers synthetic lethality in homologous recombination-deficient cells submitted to replication stress

VILLAFAÑEZ, FLORENCIA*; GARCÍA, IRIS ALEJANDRA*; CARBAJOSA, SOFIA; PANSA, MARÍA FLORENCIA; MANSILLA, SABRINA; LLORENS, MARÍA CANDELARIA; ANGIOLINI, VIRGINIA; GUANTAY, LAURA; JACOBS, HEINZ; MADAUSS, KEVIN P; GLOGER, ISRAEL; GOTTIFREDI, VANESA; BOCCO, JOSE LUIS; SORIA, GASTON

ONCOGENE

NATURE PUBLISHING GROUP

Lugar: Londres; Año: 2019

0950-9232

ranslesion DNA synthesis (TLS) and homologous recombination (HR) cooperate during S-phase to safeguard replication forks integrity. Thus, the inhibition of TLS becomes a promising point of therapeutic intervention in HR-deficient cancers, where TLS impairment might trigger synthetic lethality (SL). The main limitation to test this hypothesis is the current lack of selective pharmacological inhibitors of TLS. Herein, we developed a miniaturized screening assay to identify inhibitors of PCNA ubiquitylation, a key post-translational modification required for efficient TLS activation. After screening a library of 627 kinase inhibitors, we found that targeting the pro-survival kinase AKT leads to strong impairment of PCNA ubiquitylation. Mechanistically, we found that AKT-mediated modulation of Proliferating Cell Nuclear Antigen (PCNA) ubiquitylation after UV requires the upstream activity of DNA PKcs, without affecting PCNA ubiquitylation levels in unperturbed cells. Moreover, we confirme