Parental histone deposition on the replicated strands promotes error-free DNA damage tolerance and regulates drug resistance

Ctf4 is a conserved replisome component with multiple roles in DNA metabolism. To investigate connections between Ctf4-mediated processes involved in drug resistance, we conducted a suppressor screen of ctf4 Delta sensitivity to the methylating agent MMS. We uncovered that mutations in Dpb3 and Dpb4 components of polymerase epsilon result in the development of drug resistance in ctf4 Delta via their histone-binding function. Alleviated sensitivity to MMS of the double mutants was not associated with rescue of ctf4 Delta defects in sister chromatid cohesion, replication fork architecture, or template switching, which ensures error-free replication in the presence of genotoxic stress. Strikingly, the improved viability depended on translesion synthesis (TLS) polymerase-mediated mutagenesis, which was drastically increased in ctf4 dpb3 double mutants. Importantly, mutations in Mcm2-Ctf4-Pol alpha and Dpb3-Dpb4 axes of parental (H3-H4)(2) deposition on lagging and leading strands invariably resulted in reduced error-free DNA damage tolerance through gap filling by template switch recombination. Overall, we uncovered a chromatin-based drug resistance mechanism in which defects in parental histone transfer after replication fork passage impair error-free recombination bypass and lead to up-regulation of TLS-mediated mutagenesis and drug resistance. In this study, Dolce et al. investigated connections between Ctf4-mediated processes involved in drug resistance, and conducted a suppressor screen of ctf4 Delta sensitivity to the methylating agent MMS. Their findings demonstrate a chromatin-based drug resistance mechanism in which defects in parental histone transfer after replication fork passage impair error-free recombination bypass and lead to up-regulation of TLS-mediated mutagenesis and drug resistance.

Automated summary

In this study, the connections between Ctf4-mediated processes involved in drug resistance were investigated by conducting a suppressor screen of ctf4 Delta sensitivity to the methylating agent MMS. The findings demonstrate a chromatin-based drug resistance mechanism in which defects in parental histone transfer after replication fork passage impair error-free recombination bypass and lead to up-regulation of TLS-mediated mutagenesis and drug resistance.