PXD009524

PXD009524 is an original dataset announced via ProteomeXchange.

Title	DNA mismatch repair activity of MutLα is regulated by CK2-dependent phosphorylation of MLH1 (S477)
Description	MutLα, a heterodimer consisting of MLH1 and PMS2, is a key player of DNA mismatch repair (MMR), yet little is known about its regulation. In this study, we used mass spectrometry to identify phosphorylated residues within MLH1 and PMS2. The most frequently detected phosphorylated amino acid was serine 477 of MLH1. Isolation of nuclear and cytoplasmic fractions showed that p-MLH1S477 remains predominantly in the cytoplasm. Pharmacological treatment indicates‎ that Casein Kinase II (CK2) could be responsible for the phosphorylation of MLH1 at serine 477 in vivo. In vitro kinase assay verified MLH1 as a substrate of CK2. Most importantly, using in vitro MMR assay we could demonstrate that p-MLH1S477 lost MMR activity while the activity of MLH1S477A, which could not be phosphorylated at position S477, was not modified. In summary, we identified that post-translational phosphorylation of MLH1 by CK2 at amino acid position 477 can switch off MMR activity in vitro. Since CK2 is overexpressed in many tumors and is able to inactivate MMR by phosphorylation of MLH1, the new mechanism here described could have an important impact on tumors overactive in CK2.
HostingRepository	PRIDE
AnnounceDate	2018-08-28
AnnouncementXML	Submission_2018-08-28_08:05:03.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Angela Brieger
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	phosphorylated residue
Instrument	LTQ Orbitrap Velos

Revision	Datetime	Status	ChangeLog Entry
0	2018-04-17 08:38:03	ID requested
⏵ 1	2018-08-28 08:05:04	announced

We, ß, becher IM, Hinrichsen I, Funke S, Oellerich T, Plotz G, Zeuzem S, Grus FH, Biondi RM, Brieger A, is regulated by CK2-dependent phosphorylation of MLH1 (S477). Mol Carcinog, 57(12):1723-1734(2018) [pubmed]

curator keyword: Biological

submitter keyword: DNA mismatch repair, MLH1, MutLα, phosphorylation, CK2, Lynch syndrome

Angela Brieger
contact affiliation	University Clinic of Frankfurt Medical Clinic I Biomedical Research Laboratory Germany
contact email	a.brieger@em.uni-frankfurt.de
lab head
Angela Brieger
contact affiliation	University Clinic of Frankfurt Medical Clinic I Biomedical Research Laboratory
contact email	a.brieger@em.uni-frankfurt.de
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD009524
     1. Label: PRIDE project
     2. Name: DNA mismatch repair activity of MutLα is regulated by CK2-dependent phosphorylation of MLH1 (S477)