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

MARINA ALEJANDRA GONZÁLEZ BESTEIRO; NICOLÁS CALZETTA; SOFÍA LOUREIRO; VANESA GOTTIFREDI

Buenos Aires

Congreso; Reunión Conjunta de Biociencias; 2017

Sociedades de Biociencias

The encounter of replication forks with DNA lesions activatesCheckpoint Kinase 1 (Chk1), which impedes replication fork breakage and inhibits firing of replication origins, reducing in turn the globalrate of DNA replication. Such modification of the replication programby 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 Chk1for survival. Thus, Chk1 inhibition has emerged as a promising anti-cancer therapy.Nevertheless, little is known about the molecular mechanismsthat follow the inhibition of Chk1. The current model proposes thatChk1 inhibition initially unleashes origin firing, which in turn negatively affects the progression of active replication forks. This modelimplies that both variables are linked in a linear pathway and thatfork progression in Chk1-inhibited cells is regulated exclusively by aglobal, nucleoplasmic signal, rather than by local signals at the fork.We will present data that challenges such model, demonstrating thatChk1 inhibition generates a local signal at replication forks that impairs their elongation rate. Therefore, we have unraveled a novelmechanism that underpins the impaired fork progression phenotypeof Chk1-inhibited cells, while it has no effect on origin firing. Ourresults thus add a layer of unprecedented complexity to our currentunderstanding of how cancer cells deal with Chk1 deficiency