Proteomics

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SPARTAN Protease and Checkpoint Kinase 1 Cross-Activation Loop Safeguards Genome Stability

ABSTRACT: DNA-protein crosslinks (DPCs) are abundant DNA lesions, which constantly challenge genome stability by interfering with DNA replication. SPARTAN (SPRTN) protease plays a central role in DPCs repair in proliferative vertebrate cells. SPRTN is a constitutive part of the DNA replication machinery and its protease activity is essential for DNA replication fork progression. How this essential protease is activated and regulated during DNA replication is not known. By using biochemical, cell biological and genetic approaches in human cell lines and Zebrafish model system, we identified that SPRTN cleaves covalently crosslinked Checkpoint kinase 1 (CHK1) from chromatin and releases CHK1 during physiological DNA replication. Proteolysed CHK1 is activated and in turn phosphorylates SPRTN. Phosphorylated SPRTN is further recruited to chromatin to proteolyse DPCs that ensures unperturbed DNA replication. Our data suggest SPRTN-CHK1 cross-activation loop is essential for genome stability.

INSTRUMENT(S): Q Exactive

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Epithelial Cell, Cell Culture

SUBMITTER: iolanda Vendrell  

LAB HEAD: Kristijan Ramadan

PROVIDER: PXD006741 | Pride | 2019-11-08

REPOSITORIES: Pride

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Dataset's files

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Action DRS
HalderTorrecillaetal._Sampledescription.pdf Pdf
QE729_MSQ946_20170214_ITORRECILLA_2_DVC-3-.raw Raw
QE729_MSQ946_20170217_ITorrecilla_P28_5_SPRTN2-2_OE-WT_3ul.raw Raw
peptides.pep_2_DVC3.xml Xml
peptides.pep_5_SPRTN2.2_.xml Xml
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Publications

The SPRTN metalloprotease is essential for DNA-protein crosslink (DPC) repair and DNA replication in vertebrate cells. Cells deficient in SPRTN protease exhibit DPC-induced replication stress and genome instability, manifesting as premature ageing and liver cancer. Here, we provide a body of evidence suggesting that SPRTN activates the ATR-CHK1 phosphorylation signalling cascade during physiological DNA replication by proteolysis-dependent eviction of CHK1 from replicative chromatin. During this  ...[more]

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