CHECKPOINT KINASE1 TRIGGERS CELL DEATH AND GENOMIC INSTABILITY BY INDEPENDENT PATHWAYS

NICOLÁS L. CALZETTA; GONZÁLEZ BESTEIRO, MARINA A.; GOTTIFREDI, VANESA

Salta

Congreso; Joint LV Annual SAIB Meeting and XIV PABMB Congress; 2019

"Sociedad Argentina de Investigación en Bioquímica y Biología Molecular" y "Panamerican Association of Biochemistry and Molecular Biology"

The DNA damage response (DDR) is a complex network of inter-dependent signaling pathways that are activated upon DNA insults to assist the completion and fidelity of DNA replication. Checkpoint Kinase 1 (Chk1) is a key mediator factor of the DDR whose inhibitors are undergoing clinical evaluation across a variety of cancers. As different lines of evidences indicate that Chk1 inhibition or loss increases replication stress, genomic instability and cell death it is currently accepted that such events happen in a lineal and interdependent fashion. The link between replicative stress and cell death has been unequivocally proven in Chk1-deficient cells, but the link between genomic instability and cell death has not been unambiguously established. Such a link is important because genomic instability can also contribute to the augmentation of intratumoral genetic heterogeneity, which implies the risk of developing resistance to the treatment. Thus, elucidating the mechanisms that trigger genomic instability and how genomic instability impacts on cell survival are of utmost importance to cancer research. In this respect, we show here that genomic instability in Chk1-deficient cells emerges from DNA damage in mitosis. In particular, we uncover an unprecedented mechanism of genomic instability that involves the cleavage of under-replicated by the structure-specific endonuclease Mus81-Eme1 during mitosis. In sharp contrast, we show that cell death results from altered replication dynamics and Mus81-Eme2-dependent cleavage of DNA in S phase. Together these results demonstrate that, in the context of Chk1 inhibition/loss, cell death is not the result of genomic instability and is not ruled by the same molecular effectors. As a consequence, cancer treatment with Chk1i leads to the enrichment of a genomically unstable subpopulation that could be prevented by inhibiting the pathway identified by us. We suggest that Chk1-directed therapies could be improved by further exploring the specific signals of genomic instability discovered by us.