Control of replication associated DNA damage responses by Mismatch Repair

Ijsselsteiijn, R. (2023)

Doctoral Thesis

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 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.

• MMR
• DNA Damage
• Lynch Syndrome
• Colorectal Cancer
• Translesion synthesis
• DNA repair

• All authors: Ijsselsteiijn, R.
• Supervisor: Tijsterman, M.
• Co-supervisor: Jansen, J.G.
• Committee: Maarel, S.M. van der; Sixma, T.K.; Vrieling, H.; Lebbink, J.H.G.
• Qualification: Doctor (dr.)
• Awarding Institution: Faculty of Medicine, Leiden University Medical Center (LUMC), Leiden University
• Date: 2023-10-26
• ISBN (print): 9789464832853