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

TY - JOUR

T1 - H4K20me0 marks post-replicative chromatin and recruits the TONSL–MMS22L DNA repair complex

AU - Saredi, Giulia

AU - Huang, Hongda

AU - Hammond, Colin M

AU - Alabert, Constance

AU - Bekker-Jensen, Simon

AU - Forne, Ignasi

AU - Reverón-Gómez, Nazaret

AU - Foster, Benjamin M

AU - Mlejnkova, Lucie

AU - Bartke, Till

AU - Cejka, Petr

AU - Mailand, Niels

AU - Imhof, Axel

AU - Patel, Dinshaw J

AU - Groth, Anja

PY - 2016/6/30

Y1 - 2016/6/30

N2 - 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 postreplicative chromatin, read by the human TONSL-MMS22L1-4 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 postreplicative 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.

AB - 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 postreplicative chromatin, read by the human TONSL-MMS22L1-4 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 postreplicative 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.

KW - Chromatin

KW - DNA Repair

KW - DNA Replication

KW - DNA-Binding Proteins

KW - Genomic Instability

KW - Histones

KW - Homologous Recombination

KW - Humans

KW - Lysine

KW - Methylation

KW - Models, Molecular

KW - Molecular Chaperones

KW - NF-kappa B

KW - Nuclear Proteins

KW - Protein Binding

KW - Protein Structure, Tertiary

KW - Journal Article

KW - Research Support, Non-U.S. Gov't

U2 - 10.1038/nature18312

DO - 10.1038/nature18312

M3 - Journal article

C2 - 27338793

SN - 0028-0836

VL - 534

SP - 714

EP - 718

JO - Nature

JF - Nature

IS - 7609

ER -