CHECKPOINT KINASE 1 IS A MASTER REGULATOR OF THE DNA REPLICATION PROGRAM IN CANCER CELLS

VANESA GOTTIFREDI; MARINA A. GONZÁLEZ BESTEIRO; SOFÍA LOUREIRO; NICOLÁS L. CALZETTA

Congreso; Reunión Biociencias 2017; 2017

The encounter of replication forks with DNA lesions activates Checkpoint Kinase 1 (Chk1), which impedes replication fork breakage and inhibits firing of replication origins, reducing in turn the global rate of DNA replication. Such modification of the replication program by the so called intra-S phase checkpoint allows cells to repair damaged DNA, promoting cell survival. Cancer cells, which are inherently challenged with high doses of replication stress, rely on Chk1 for survival. Thus, Chk1 inhibition has emerged as a promising anti-cancer therapy.Nevertheless, little is known about the molecular mechanisms that follow the inhibition of Chk1. The current model proposes that Chk1 inhibition initially unleashes origin firing, which in turn negatively affects the progression of active replication forks. This model implies that both variables are linked in a linear pathway and that fork progression in Chk1-inhibited cells is regulated exclusively by a global, nucleoplasmic signal, rather than by local signals at the fork. We will present data that challenges such model, demonstrating that Chk1 inhibition generates a local signal at replication forks that impairs their elongation rate. Therefore, we have unraveled a novel mechanism that underpins the impaired fork progression phenotype of Chk1-inhibited cells, while it has no effect on origin firing. Our results thus add a layer of unprecedented complexity to our current understanding of how cancer cells deal with Chk1 deficiency.