H4K20me0 marks post-replicative chromatin and recruits the TONSL–MMS22L DNA repair complex

Abstract

Summary 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 TONSL–MMS22L1–4 homologous recombination (HR) 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. Accordingly, TONSL–MMS22L binds new histones H3–H4 both prior to 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, this reveals a histone reader based mechanism to recognize the post-replicative state, offering a new approach and opportunity to understand DNA repair with potential for targeted cancer therapy.

Histone chaperone networks shaping chromatin function

“…An explanation for this observation is not yet available, but it may be that there are synergistic effects of co-chaperoning during H3–H4 deposition. Interestingly, histones bound to MCM2 and ASF1 can also engage TONSL 84 , which has a dual function as a histone reader and a histone chaperone 84,85 . The ankyrin repeat domain (ARD) of TONSL recognizes the basic patch of the H4 tail (K16–K20) when K20 is unmethylated (H4K20me0) 84 (FIG.…”

“…The TONSL ARD holds the H4 tail perpendicular to the DNA-binding surface of the H3–H4 tetramer and can also bind nucleosomal H4 (REF. 84). As such, TONSL ARD recognition of the H4 tail may help to guide nucleosomal DNA across the H3–H4 tetramer during deposition and potentially counteract binding of the H4 tail to the acidic patch of H2A–H2B on neighbouring nucleosomes 86 to prevent premature chromatin compaction 84 .…”

“…Highlighting its central role in chaperoning H3–H4, ASF1 forms a large number of co-chaperone complexes with H3.1, H3.2, H3.3 and one or more of the chaperones Vps75, sNASP, RBAP46, RBAP48, MCM2 and the reader and chaperone TONSL 51,76,84,85,87–91 (FIG. 4).…”

MRG15-mediated tethering of PALB2 to unperturbed chromatin protects active genes from genotoxic stress

“…For example, dimethylation of histone H4 at lysine 20 (H4K20me2) contributes to the direct recruitment of HR suppressor 53BP1 (39), whereas nonmethylated H4K20 (H4K20me0), which is only found in newly replicated DNA, plays a critical role in the recruitment of TONSL-MMS22L, promoting HR repair in S phase (40). Also, H3K36me3 supports the constitutive association of LEDGF (p75) with active genes, which upon DNA damage recruits the repair factor CtIP to facilitate HR repair (24,26).…”

MGO3 and GIP1 act synergistically for the maintenance of centromeric cohesion

“…MGO3/BRU1/TSK plays a role in stalling replication forks 12 as described for its homolog in humans, Tonsoku-Like (TONSL), 21,22 acting as a reader of new epigenetic marks linked to new histone incorporation at the post-replicative state. 23 Beside their role in centromeric cohesion, GIPs must also be involved in the loading/maintenance of CENH3 at centromeres. 7 The current challenge is to untangle the dynamics of these processes and to characterize the chaperones involved in CENH3 loading.…”