The histone H3.1 variant regulates TONSOKU-mediated DNA repair during replication

Abstract

The tail of replication-dependent histone H3.1 varies from that of replication-independent H3.3 at the amino acid located at position 31 in plants and animals, but no function has been assigned to this residue to demonstrate a unique and conserved role for H3.1 during replication. We found that TONSOKU (TSK/TONSL), which rescues broken replication forks, specifically interacts with H3.1 via recognition of alanine 31 by its tetratricopeptide repeat domain. Our results indicate that genomic instability in the absence of ATXR5/ATXR6-catalyzed histone H3 lysine 27 monomethylation in plants depends on H3.1, TSK, and DNA polymerase theta (Pol θ). This work reveals an H3.1-specific function during replication and a common strategy used in multicellular eukaryotes for regulating post-replicative chromatin maturation and TSK, which relies on histone monomethyltransferases and reading of the H3.1 variant.

The TRIPLE PHD FINGERS proteins are required for SWI/SNF complex-mediated +1 nucleosome positioning and 5’ transcript length determination in Arabidopsis

“…Moreover, it serves as a recruitment platform for multiple histone reader proteins (2). Thus, nucleosomes play an important role in the regulation of chromatin affecting diverse processes such as transcription, replication, and repair (3)(4)(5).…”

The Role of the TSK/TONSL-H3.1 Pathway in Maintaining Genome Stability in Multicellular Eukaryotes

“…The identification of TSK/TONSL as DNA repair proteins rescuing broken replication forks, the reported interaction between TONSL and histone H3, and the role of ATXR5/6 in maintaining genome stability in plants via H3.1K27me1 during replication all pointed to a possible link between these proteins. The functional relationship between H3.1, ATXR5/6, and TSK/TONSL was confirmed in a recent study that showed that TSK acts as an H3.1 reader protein via a conserved tetratricopeptide repeat (TPR) domain [ 57 ]. The TPR domain in TSK is composed of 11 repeated TPR motifs (hairpins of antiparallel α-helices) that fold into a channel-like solenoid ( Figure 3 B) [ 57 ].…”

“…The H3K27 monomethyltransferases ATXR5 and ATXR6 (ATXR5/6), which are represented in all land plants and Tetrahymena thermophila [ 55 , 56 ] but are absent in animals, were the first histone-modifying enzymes shown to specifically methylate the H3.1 variant [ 56 ]. A recent follow-up study related to ATXR5/6 has revealed a universal H3.1 reader domain in the protein TONSOKU (TSK) (known as TONSOKU-LIKE/TONSL in animals), which participates in the regulation of DNA repair during replication [ 57 ]. The discoveries of proteins that can write or read H3.1 are presented in greater depth in the next sections.…”

“…However, it was unclear whether or not such a role for H3.1 would be conserved in animals. The recent identification of the DNA repair protein TSK/TONSL as an H3.1 reader protein provides new insights into these questions [ 57 ].…”

“…In addition, mammalian TONSL was shown to directly interact with H4K20me0 via its ankyrin repeat domain (ARD), which plays an essential role in recruiting TONSL to chromatin to mediate DNA repair during replication ( Figure 3 A) [ 78 ]. Interestingly, the ARD domain is absent from the plant TSK proteins [ 57 , 73 ], thus suggesting that TSK and TONSL are recruited to chromatin through different mechanisms.…”