PXD011328

PXD011328 is an original dataset announced via ProteomeXchange.

Title	Histone H3 Serine-57 phosphorylation by CHK1 promotes responses to DNA replication stress
Description	Post-translational modifications (PTM) of chromatin control the genomic environment for transcription, DNA replication and repair in response to cell stimuli1–3. Replication stress in budding and fission yeasts leads to abundant acetylation of histone H3 on lysine-56 (H3K56ac)4–6, but only trace levels of H3K56ac are detected in human cells7,8, implying that other histone modifications promote a repair-permissive environment. In budding yeast, genetic interactions between histone H3 lysine-56 and serine-57 substitutions suggest a possible role for serine-57 (H3S57) in responses to replication poisons9. In this study, we identify a phosphorylated form of H3S57 (H3S57ph) using phosphoproteomics in replicating Xenopus egg extracts, and show that it is a highly conserved histone modification which promotes responses to DNA replication stress in human cells. A kinome screen and functional experiments identified Checkpoint kinase 1 (CHK1) as the H3S57ph kinase; CHK1 inhibition eliminates H3S57ph and arrests cells in S-phase. Induction of replication stress increases H3S57ph, while disrupting H3S57ph reduces stalling of replication forks upon replication stress, inducing DNA damage. We identified two distinct mechanisms of action. First, H3S57ph interacts with specific DNA repair proteins, notably Rad50. Second, atomistic molecular dynamics simulations of the nucleosome core particle and in vitro assays indicate that H3S57ph interacts with the unacetylated side-chain of K56, thus loosening DNA-histone contacts. Our results suggest that H3S57ph is an effector of CHK1 that assists in processing stalled replication forks by increasing nucleosome mobility and promoting interactions with repair machinery, thereby limiting DNA damage upon replication stress.
HostingRepository	PRIDE
AnnounceDate	2022-02-10
AnnouncementXML	Submission_2022-02-10_01:46:51.268.xml
DigitalObjectIdentifier	https://dx.doi.org/10.6019/PXD011328
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Supported dataset by repository
PrimarySubmitter	sonia hem
SpeciesList	scientific name: Xenopus laevis (African clawed frog); NCBI TaxID: 8355; scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	Phospho; Oxidation; Acetyl; Carbamidomethyl
Instrument	Q Exactive

Revision	Datetime	Status	ChangeLog Entry
0	2018-10-10 05:30:56	ID requested
⏵ 1	2022-02-10 01:46:51	announced

Dataset with its publication pending

curator keyword: Biological

submitter keyword: DNA replication stress, histone post-translational modifications, H3S57ph, Checkpoint kinase 1 (Chk1), chromatin

Daniel Fisher
contact affiliation	IGMM, CNRS, University of Montpellier, Montpellier, France Ligue Nationale Contre le Cancer team
contact email	daniel.fisher@igmm.cnrs.fr
lab head
sonia hem
contact affiliation	INRA
contact email	sonia.hem@supagro.inra.fr
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD011328
     1. Label: PRIDE project
     2. Name: Histone H3 Serine-57 phosphorylation by CHK1 promotes responses to DNA replication stress