Abstract

Targeting Homologous Recombination Repair In Cancer: Structure-Based Drug Design On A New Histone Reader

Anja Groth, Group Leader, University of Copenhagen

After DNA replication, chromosomal processes including DNA repair and transcription take place in the context of sister chromatids. While cell cycle regulation can guide these processes globally, mechanisms to distinguish pre- and post-replicative states locally can be important to guide repair pathway choice. We have recently discovered that new histones incorporated during DNA replication provide a signature of post-replicative chromatin, read by the TONSL–MMS22L homologous recombination complex. We identify the TONSL Ankyrin Repeat Domain (ARD) as a reader of histone H4 tails unmethylated at K20 (H4K20me0), which are specific to new histones incorporated during DNA replication and mark post-replicative chromatin until G2/M. H4K20me0 recognition is required for TONSL–MMS22L binding to chromatin and accumulation at challenged replication forks and DNA lesions. This reveals a histone reader based mechanism to recognize the post-replicative state, offering a new opportunity to target homologous recombination repair in cancer therapy.