PXD055315-1

PXD055315 is an original dataset announced via ProteomeXchange.

Title	Lactylation of XLF Promotes NHEJ Activity and Contributes to Chemo-Resistance in Cancer
Description	Both 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.
HostingRepository	iProX
AnnounceDate	2024-08-27
AnnouncementXML	Submission_2024-08-28_20:31:40.942.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Mingpeng Jin
SpeciesList	scientific name: Homo sapiens; NCBI TaxID: 9606;
ModificationList	acetylated residue
Instrument	timsTOF Pro

Revision	Datetime	Status	ChangeLog Entry
0	2024-08-28 20:31:31	ID requested
⏵ 1	2024-08-28 20:31:41	announced

Dataset with its publication pending

submitter keyword: Lactylation, the warburg effect, XLF, cell-penetrating peptide, chemoresistance, non-homologous end joining repair, lactylation

Jian Yuan
contact affiliation	Tongji University School of Medicine
contact email	yuanjian229@hotmail.com
lab head
Mingpeng Jin
contact affiliation	Tongji University School of Medicine
contact email	1285373533@qq.com
dataset submitter

iProX dataset URI