Polymerase iota prevents PrimPol-mediated nascent DNA synthesis and chromosome instability.

MANSILLA SF, BERTOLIN AP, VENERUS ARBILLA S, CASTAÑO BA, JAHJAH T, SINGH JK, SIRI SO, CASTRO MV, DE LA VEGA MB, QUINET A, WIESMÜLLER L, GOTTIFREDI V.

Science Advances

Science Advances is the American Association for the Advancement of Science

Año: 2023

2375-2548

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 use of tools for their depletion, we identified a unique role of Pol iota in regulating such a pathway choice. Pol iota deficiency unleashes PrimPol-dependent repriming, which accelerates DNA replication in a pathway that is epistatic with ZRANB3 knockdown. In Pol iota 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  requires its PCNA interacting but not its polymerase domain. Our findings unravel an unanticipated role of Pol iota in protecting the genome stability of cells from detrimental changes in DNA replication dynamics caused by PrimPol.