ovel regulators of the replication of damaged DNA.

MANSILLA S, SPERONI J, FEDERICO MB, VALLERGA MB, HABIF M AND GOTTIFREDI V.

San Luis

Congreso; XLVII Reunión Anual de la Sociedad Argentina de Investigación en Bioquímica y Biología Molecular.; 2011

Novel regulators of the replication of damaged DNA S Mansilla, J Speroni, MB Federico, MB Vallerga, M Habif and V Gottifredi Cell Cycle and Genomic Stability Laboratory, Fundación Instituto Leloir, CONICET, UBA, BA, Argentina While it is clear that DNA lesions trigger the activation of many signalling pathways that aid DNA replication, the levels of coordination between such pathways are unknown.  On one hand, stalled forks trigger the activation of checkpoint signals to globally reduce DNA synthesis. On the other hand, translesion DNA synthesis (TLS) avoids fork stalling using DNA lesions as templates. While TLS promotes the maintenance of DNA replication on individual replicating forks, one single stalling event spreads a checkpoint-induced warning signal to other replicating forks. Both pathways are activated in the same cells but it is unknown if they can coordinate their action at single replicating forks. We have recently found that two molecules associated to checkpoint activation can influence TLS activation. We have accumulated evidence indicating that a checkpoint target, the cyclin kinases inhibitor p21, is a negative regulator of TLS associated events. Also, we have found that a central checkpoint effector kinase, Chk1, positively modulates the same events. Intriguingly the PCNA domain of both proteins is required for their action on TLS. Thus, we propose that the crosstalk between molecules in both pathways might determine the timing of their activation at forks that encounter DNA lesions.