Polymerase iota (Pol ι) prevents PrimPol-mediated nascent DNA synthesis and chromosome instability

MANSILLA, SABRINA FLORENCIA; BERTOLIN AGOSTINA; SOFIA VENERUS ARBILLA; CASTAÑO, BRYAN; TIYA JAHJAH; JENNY K. SINGH; SEBASTIÁN OMAR SIRI; MARIA VICTORIA CASTRO ; MARIA BELEN DE LA VEGA; ANNABEL QUINET ; WIESMÜLLER, LISA; VANESA GOTTIFREDI

Science Advances

Science Advances is the American Association for the Advancement of Science

Lugar: washington; Año: 2023

2375-2548

Recent studies havedescribed a DNA damage tolerance pathway choice that involves a competitionbetween PrimPol-mediated repriming and fork reversal. Screening differentTranslesion DNA synthesis (TLS) polymerases by use of tools for theirdepletion, we identified a unique role of Pol i in regulating such a pathway choice. Pol i deficiency unleashes PrimPol-dependent repriming,which accelerates DNA replication in a pathway that is epistatic with ZRANB3knockdown. In Pol i depleted cells, the excess participation of PrimPol in nascent DNAelongation reduces replication stress signals, but thereby also checkpointactivation in S phase, triggering chromosome instability in M phase. ThisTLS-independent function of Pol i requires its PCNA interacting but not its polymerase domain. Ourfindings unravel an unanticipated role of Pol i in protecting the genome stability of cellsfrom detrimental changes in DNA replication dynamics caused by PrimPol.