Mismatch repair (MMR) is a DNA repair system that corrects base-base misincorporations generated by the replicative DNA polymerases. Previous publications have shown the involvement of the MMR... Show moreMismatch repair (MMR) is a DNA repair system that corrects base-base misincorporations generated by the replicative DNA polymerases. Previous publications have shown the involvement of the MMR pathway in control of DNA damage responses. The work presented in this thesis suggests that the regulation of DNA damage induced mutagenesis and signaling may lie in the complex interplay between translesion synthesis (TLS), a subset of error-prone polymerases capable of replicating damaged DNA, and MMR. This thesis suggests that MMR may reduce DNA damage induced mutagenesis via two ways: (i) recruit the somewhat less error-prone TLS polymerases to the DNA lesion and (ii) post-replicative removal of mismatched nucleotides. Of note, inheriting a heterogenous defect in an MMR gene results in increased risk of developing cancer, in particular colorectal cancer. The reason for this specific cancer tropism is, as of yet, unclear. The colorectal tract is continuously exposed to DNA damaging agents and indeed data in this thesis shows that MMR is important in protecting against diet-derived DNA damaging agents by controlling DNA damage induced mutagenesis and signaling. As such the colorectal cancer tropism of MMR of LS may partly be explained by the role of MMR in controlling the DNA damage response. Show less
In this thesis I describe the developmental role of the Y-family polymerases Pol Eta, Pol Kappa and Rev1 in protection against exogenous and endogenous damage in C. elegans. Furthermore I identify... Show moreIn this thesis I describe the developmental role of the Y-family polymerases Pol Eta, Pol Kappa and Rev1 in protection against exogenous and endogenous damage in C. elegans. Furthermore I identify a new role for the A-family Polymerase Pol Theta in repair of replication-associated breaks. Show less
Krijger, P.H.L.; Tsaalbi-Shtylik, A.; Wit, N.; Berk, P.C.M. van den; Wind, N. de; Jacobs, H. 2013
To protect the genome, cells have evolved a diverse set of pathways designed to sense, signal, and repair multiple types of DNA damage. To assess the degree of coordination and crosstalk among... Show moreTo protect the genome, cells have evolved a diverse set of pathways designed to sense, signal, and repair multiple types of DNA damage. To assess the degree of coordination and crosstalk among these pathways, we systematically mapped changes in the cell's genetic network across a panel of different DNA-damaging agents, resulting in ~1,800,000 differential measurements. Each agent was associated with a distinct interaction pattern, which, unlike single-mutant phenotypes or gene expression data, has high statistical power to pinpoint the specific repair mechanisms at work. The agent-specific networks revealed roles for the histone acetyltranferase Rtt109 in the mutagenic bypass of DNA lesions and the neddylation machinery in cell-cycle regulation and genome stability, while the network induced by multiple agents implicates Irc21, an uncharacterized protein, in checkpoint control and DNA repair. Our multiconditional genetic interaction map provides a unique resource that identifies agent-specific and general DNA damage response pathways. Show less
Krijger, P.H.L.; Berk, P.C.M. van den; Wit, N.; Langerak, P.; Jansen, J.G.; Reynaud, C.A.; ... ; Jacobs, H. 2011
