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PXD055315

PXD055315 is an original dataset announced via ProteomeXchange.

Dataset Summary
TitleLactylation of XLF Promotes NHEJ Activity and Contributes to Chemo-Resistance in Cancer
DescriptionBoth metabolism reprogramming and DNA damage repair play critical roles in tumorigenesis and chemoresistance. However, the underlying mechanism linking the two pathways remains elusive. Here, we show that loss of lactate dehydrogenase A (LDHA) impairs non-homologous end joining (NHEJ) repair and reduces class switch recombination (CSR) in mice. In addition, we found that lactate, a metabolite of glycolysis, is involved in the regulation of NHEJ repair via XLF lactylation modification. Mechanically, upon DNA damage, GCN5 is phosphorylated by ATM, which promotes the interaction between GCN5 and XLF and stimulates the lactylation modification of XLF K288, which locates within the XLF Ku-binding motif (X-KBM). XLF lactylation enhances its interaction with Ku80, promotes XLF recruitment to DNA damage sites and elevates NHEJ efficiency. We solved the cryo-EM structure of Ku70/80 in complex with lactylated X-KBM (laX-KBM) and identified a new binding mode between Ku70/80 and XLF. laX-KBM interacts with Ku80 in a stretched and extended mode, resulting in conformational changes of the Ku80 vWA domain. Moreover, XLF lactylation deficiency impairs NHEJ and sensitizes cancer cells to chemotherapy. We designed a peptide specifically inhibiting XLF K288 lactylation, and combination of this peptide with 5-fluorouracil (5-FU) kill colorectal cancer cells more efficiently in PDX model with hyperactivation of XLF lactylation. Together, these results suggest that GCN5-XLF lactylation axis plays a key role in NHEJ stimulation and that targeting XLF lactylation might be a promising approach to improve chemotherapy efficiency in cancer.
HostingRepositoryiProX
AnnounceDate2024-08-27
AnnouncementXMLSubmission_2024-08-28_20:31:40.942.xml
DigitalObjectIdentifier
ReviewLevelPeer-reviewed dataset
DatasetOriginOriginal dataset
RepositorySupportUnsupported dataset by repository
PrimarySubmitterMingpeng Jin
SpeciesList scientific name: Homo sapiens; NCBI TaxID: 9606;
ModificationListacetylated residue
InstrumenttimsTOF Pro
Dataset History
RevisionDatetimeStatusChangeLog Entry
02024-08-28 20:31:31ID requested
12024-08-28 20:31:41announced
Publication List
Dataset with its publication pending
Keyword List
submitter keyword: Lactylation, the warburg effect, XLF, cell-penetrating peptide, chemoresistance, non-homologous end joining repair, lactylation
Contact List
Jian Yuan
contact affiliationTongji University School of Medicine
contact emailyuanjian229@hotmail.com
lab head
Mingpeng Jin
contact affiliationTongji University School of Medicine
contact email1285373533@qq.com
dataset submitter
Full Dataset Link List
iProX dataset URI