THE ALTERNATIVE DNA POLYMERASE IOTA PROMOTES CHECKPOINT ACTIVATION.

BERTOLIN AP, MANSILLA SF, CAMPODÓNICO P, CALZETTA N, DE LA VEGA MB AND GOTTIFREDI V

Roma

Conferencia; FUSION CONFERENCE. 2nd DNA replication as a source of DNA damage: from molecules to human health.; 2017

THE ALTERNATIVE DNA POLYMERASE IOTA PROMOTES CHECKPOINT ACTIVATIONAgostina P. Bertolin*, Sabrina F. Mansilla*, Paola Campodónico, Nicolás Calzetta, María Belén de la Vega and Vanesa Gottifredi. *equal collaboration Fundación Instituto Leloir. Instituto de Investigaciones Bioquímicas de Buenos Aires, Argentina. Consejo Nacional de Investigaciones Científicas y TécnicasVanesa GottifrediThe DNA damage response (DDR) is a multifaceted network of signals which is activated by structural and chemical alterations of the DNA. The DDR involves DNA repair, DNA damage tolerance and checkpoint pathways which act in coordination. The level of crosstalk between DDR pathways has been partially revealed. For instance, it is accepted that DNA damage tolerance by alternative DNA polymerases facilitate DNA replication across DNA lesions hence preventing structural changes at replication forks known to trigger checkpoint activation. It is unclear if all alternative DNA polymerases have complete overlapped functions. Here we show that, the alternative polymerase iota (pol ), but no other alternative pols, has a role in checkpoint activation which is unrelated to its function in DNA damage tolerance. Instead of facilitating DNA elongation across DNA lesions, pol reduces nascent DNA synthesis, increasing the levels of checkpoint-inducing RPA-coated DNA. Pol depletion also causes a down-modulation of checkpoint signals such as H2AX and 53BP1 foci formation, and Chk1 kinase activation. In pol -depleted samples, such a defect in checkpoint activation is associated with increased levels of origin firing, cell death and genomic instability. Hence, pol may be key for an efficient contribution of the checkpoint to DDR