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 remain unknown. Here we reveal that new histones incorporated during DNA replication provide a signature of post-replicative chromatin, read by the human TONSL–MMS22L1,2,3,4 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 the G2/M phase of the cell cycle. Accordingly, TONSL–MMS22L binds new histones H3–H4 both before and after incorporation into nucleosomes, remaining on replicated chromatin until late G2/M. H4K20me0 recognition is required for TONSL–MMS22L binding to chromatin and accumulation at challenged replication forks and DNA lesions. Consequently, TONSL ARD mutants are toxic, compromising genome stability, cell viability and resistance to replication stress. Together, these data reveal a histone-reader-based mechanism for recognizing the post-replicative state, offering a new angle to understand DNA repair with the potential for targeted cancer therapy.
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Protein Data Bank
Coordinate and structure factors have been deposited in the Protein Data Bank under accession number 5JA4.
We thank the beam staff at the synchrotrons at the Argonne National Laboratory (NE-CAT) for technical assistance. We thank J. Rouse, D. Durocher, G. Legube and C. Storgaard Sørensen for reagents, G. Montoya for assistance with circular dichroism, C. B. Strømme, A. Strandsby, K. Nakamura, S.-b. Lee and M. Hödl for help with experiments, and Y. Antoku for assistance with microscopy. We thank J. Lukas for comments on the manuscript and Z. Jasencakova for illustrations. G.S. was supported by European Commission Marie Curie ITN FP7 ‘aDDRess’. D.J.P. was supported in part by grants from the Leukemia and Lymphoma Society and the STARR foundation. A.G. is an EMBO Young Investigator and her research is supported by the European Research Council (ERC StG, no. 281765), the Danish National Research Foundation to the Center for Epigenetics (DNRF82), the Danish Cancer Society, the Danish Medical Research Council, the Novo Nordisk Foundation and the Lundbeck Foundation. A.I. is supported by the European Commission FP7 Network of Excellence EpiGeneSys (project 257082), the DFG Excellence Clusters CIPSM and SyNergy, as well as the DFG Collaborative Research Center 1064 (projects A3 and Z3). T.B. is supported by the Medical Research Council and the European Research Council (ERC StG, no. 309952).
Extended data figures
Extended data tables
This file contains Supplementary Figure 1, the uncropped scans with size marker indications.