A site-specific analysis of the ADP-Ribosylome unveils Homogeneous Serine ADP-Ribosylation across wild-type and BRCA-mutant Breast Cancer cell lines
Ontology highlight
ABSTRACT: ADP-ribosylation (ADPr) signaling plays a crucial role in the DNA damage response. Inhibitors against the main enzyme catalyzing ADPr after DNA damage – PARP1 – are used as targeted therapies against breast cancers with BRCA1/2 mutations. However, development of resistance to PARP inhibitors (PARPi) is a major obstacle in treating patients. To better understand the role of ADPr in PARPi sensitivity, we used Liquid Chromatography-Mass Spectrometry (LC-MS) for systems level analysis of the ADP-ribosylome in six breast cancer cell lines with different PARPi sensitivities. We identified 1632 sites on 777 proteins, primarily on serine residues, with a high site overlap of DNA damage-related proteins across all cell lines, demonstrating high conservation in ADPr signaling after DNA damage. We furthermore observed site-specific differences in ADPr intensities in PARPi-sensitive BRCA mutants, and unique ADPr sites in PARPi-resistant BRCA mutant cells, which we notably show to have low PARG levels and longer PARP1 ADPr chains.
INSTRUMENT(S): Orbitrap Fusion Lumos, Orbitrap Exploris 480
ORGANISM(S): Homo Sapiens (human)
TISSUE(S): Permanent Cell Line Cell, Cell Culture
DISEASE(S): Breast Cancer
SUBMITTER: Holda Anagho
LAB HEAD: Michael Lund Nielsen
PROVIDER: PXD047613 | Pride | 2024-08-02
REPOSITORIES: Pride
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