The TONSL–MMS22L DNA Repair Complex Is a H4K20me0 Reader

The mechanisms by which cells distinguish and recognize prereplicative and postreplicative chromatin states are poorly understood. The TONSL–MMS22L homologous recombination complex has been shown to interact not only with nucleosomal histones in chromatin but also with newly synthesized histone H3 and H4, the histone chaperone ASF1, and the replication factor MCM2, suggesting functions for TONSL–MMS22L as both a histone code reader and a histone chaperone during DNA replication. Finding that the TONSL ankyrin repeat domain (ARD) alone bound directly to histones H3 and H4, Saredi, Huang, and colleagues solved the crystal structure of the TONSL ARD in complex with an H3–H4 tetramer and the MCM2 histone-binding domain and observed that the TONSL ARD interacted with the H4 tail. Of note, the structure predicted that H4K20 methylation would disrupt essential hydrogen bonds between the TONSL ARD and H4 tails. Consistent with this prediction, TONSL-bound nucleosomes did not exhibit H4K20 methylation, and depletion of the H4K20 methyltransferase SET8 increased TONSL binding to chromatin sites that normally exhibit H4K20 methylation, providing further evidence that TONSL binds to unmethylated H4K20 (H4K20me0). Altogether, these findings suggest a role for the TONSL ARD as a histone-reading domain for H4K20me0 as well as a role for the TONSL–MMS22L complex in recognizing postreplicative chromatin, as the majority of newly synthesized histones, but not recycled histones, are unmethylated at H4K20. TONSL was recruited to DNA repair sites and damaged replication forks during S and G2 phases, but was excluded from chromatin in G1 phase, further indicating that TONSL is recruited to replication forks and postreplicative chromatin by recognition of H4K20me0. Additionally, TONSL ARD mutants induced replication-associated DNA damage, whereas the recruitment of wild-type TONSL–MMS22L to chromatin maintained genome stability in the presence of DNA damaging agents. In addition to suggesting a tumor-suppressive function of TONSL–MMS22L in recognizing H4K20me0, these findings provide a histone-based mechanism for recognizing postreplicative chromatin.

Saredi G, Huang H, Hammond CM, Alabert C, Bekker-Jensen S, Forne I, et al. H4K20me0 marks post-replicative chromatin and recruits the TONSL-MMS22L DNA repair complex. Nature 2016;534:714–8.

• ©2016 American Association for Cancer Research.