Polymerase iota (Pol ι) prevents PrimPol-mediated nascent DNA synthesis and chromosome instability
Sabrina F. Mansilla, Agostina P. Bertolin, Sofía Venerus Arbilla, Bryan A. Castaño, Tiya Jahjah, Jenny Kaur Singh, Sebastián Omar Siri, María Victoria Castro, María Belén de la Vega, Annabel Quinet, Lisa Wiesmüller, Vanesa Gottifredi
Abstract
Recent studies have described a DNA damage tolerance pathway choice that involves a competition between PrimPol-mediated repriming and fork reversal. Screening different translesion DNA synthesis (TLS) polymerases by the use of tools for their depletion, we identified a unique role of Pol ι in regulating such a pathway choice. Pol ι deficiency unleashes PrimPol-dependent repriming, which accelerates DNA replication in a pathway that is epistatic with ZRANB3 knockdown. In Pol ι-depleted cells, the excess participation of PrimPol in nascent DNA elongation reduces replication stress signals, but thereby also checkpoint activation in S phase, triggering chromosome instability in M phase. This TLS-independent function of Pol ι requires its PCNA-interacting but not its polymerase domain. Our findings unravel an unanticipated role of Pol ι in protecting the genome stability of cells from detrimental changes in DNA replication dynamics caused by PrimPol.