The specialized DNA polimerase iota coordinates DNA replication and checkpoint activation.

ERTOLIN A, MANSILLA SF, DE LA VEGA MB, VENERUS ARBILLA S, GOTTIFREDI V

Seefeld

Workshop; EMBO WORKSHOP, Modularity of Signaling proteins and networks.; 2018

EMBO

Specialized DNA polimerase iota coordinates DNA replication andcheckpoint activationAgostina P. Bertolin, Sabrina F. Mansilla, María Belén de la Vega, Sofia VenerusArbilla, Vanesa GottifrediFundación Instituto Leloir. IIBBA. CONICET, Buenos AIres, ArgentinaThe DNA damage response (DDR) is a multifaceted network of signals which isactivated by structural and chemical alterations of the DNA. Between others, central pathways for DDR are the DNA damage tolerance by specialized DNA polymerases and the checkpoint. It is unclear if all specialized DNA polymerases have complete overlapped functions. Here we show that the alternative polymerase iota, but no other alternative pols, has a role in checkpoint activation which is unrelated to a role in DNA damage tolerance. In pol iota depleted samples, nascent DNA elongation increases being such accelerated elongation symmetric in speed. In addition, pol iota depleted samples show lower levels of single-stranded DNA (ssDNA) accumulation implying that elongation of DNA is continuous. While nascent DNA elongation seems untroubled by pol iota depletion, the low levels of ssDNA correlate with a global reduction on DDR markers including chromatin-bound RPA, gamma H2AX, 53BP1, phosphoKap1 and even Chk1 activation. Defective DDR in the absence of pol iota triggers excessive origin firing which in turn causes increased genomic instability of pol iota-depleted cells. Our results reveal a crucial role of pol iota in the coupling of nascent DNA elongation and the generation of ssDNA?mediated DDR signals. Sucha novel function of pol iota is relevant for the genomic stability and the survival of cells.