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H4 K20me0 marks post-replicative chromatin and recruits the TONSL-MMS22L DNA repair complex
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...
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Published in: | Nature (London) 2016-06, Vol.534 (7609), p.714-718 |
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Main Authors: | , , , , , , , , , , , , , , |
Format: | Article |
Language: | English |
Online Access: | Get full text |
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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–MMS22L
1
–
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. |
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ISSN: | 0028-0836 1476-4687 |
DOI: | 10.1038/nature18312 |