The specialized DNA polymerase iota promotes checkpoint activation by controlling nascent DNA elongation speed

BERTOLIN A, MANSILLAS,DE LAVEGA MB, VENERUS ARBILLA S, HAMPP S, WIESMULLER L AND GOTTIFREDI V

Karlsruhe

Congreso; Annual Meeting of the German Society of DNA repair.; 2018

Sociedad alemana de reparación de ADN

The specialized DNA polymerase iota promotes checkpoint activation by controlling nascent DNA elongation speedAgostina Bertolin1, Sabrina Mansilla1, María Belén de la Vega1, Sofía Venerus Arbilla1, Sthephanie Hampp2, Lisa Wiesmuller2 and Vanesa Gottifredi1The DNA damage response (DDR) is a multifaceted network of signals which is activated by structural and chemical alterations of the DNA. Between others, pathways crucial for a correct DDR are: a) the DNA damage tolerance by specialized DNA polymerases and b) the checkpoint. The level of interconnection between DNA damage tolerance and checkpoint is unknown.It is also unclear all specialized DNA polymerases are exclusively involved in the activation of DNA damage tolerance events. 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 is faster being such accelerated elongation symmetric in speed, even on damaged DNA templates. In correlation with the apparently untroubled yet faster elogation of nascent DNA in pol iota depleted samples, a global reduction on DDR markers including chromatin-bound RPA, gamma H2AX, 53BP1, phosphoKap1 and even Chk1 activation was observed. Defective DDR in the absence of pol iota triggered excessive origin firing which in turn caused 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 RPA?mediated checkpoint signals. Such a novel function of pol iota is relevant for the genomic stability and the survival of cells