REV1 Coordinates a Multi-Faceted Tolerance Response to DNA Alkylation Damage and Prevents Chromosome Shattering in Drosophila melanogaster .

Organisms have evolved several ways to continue copying their DNA when it is damaged, grouped into the categories of translesion synthesis and template switching. These damage tolerance mechanisms prevent replication forks from collapsing when they encounter DNA damage and prevent catastrophic genome instability and cell death. While the proteins and pathways involved in damage tolerance are beginning to be understood at the single cell level, how they are regulated in multicellular organisms is an intriguing question. In this study, we investigated the mechanisms by which Drosophila tolerate alkylation damage during their development. We discovered that tissues containing rapidly dividing diploid cells favor translesion synthesis over template switching, preferentially utilizing different translesion polymerases in a context-dependent manner. Furthermore, we showed that the REV1 protein, best known for its role in recruiting translesion DNA polymerases to damage sites, performs multiple functions during damage tolerance. Together, our results demonstrate that damage tolerance preferences for multicellular organisms may differ from those observed in cultured cells, and establish Drosophila as a useful model system for studying tolerance mechanisms.