Proteomics

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DNA damage stress control is a tLT- and EHMT2-dependent central feature of Merkel Cell Carcinoma


ABSTRACT: Merkel cell carcinoma (MCC) is an aggressive skin cancer with a high mortality rate. Merkel cell polyomavirus (MCPyV) is the etiology of 80% of MCC cases via expression of the viral oncogenes small T antigen (sT) and truncated large T antigen (tLT). These proteins impair the Rb1-dependent G1/S checkpoint blockade and subvert the host cell epigenome to promote proliferation and evade immune detection. Through whole proteome analysis and proximal interactomics, we identified a tLT-dependent deregulation of DNA damage response (DDR) proteins. We investigated a novel protein proximal interaction between tLT and the histone methyltransferase EHMT2. In this regard, TA knockdown in MCC cells reduced DDR protein levels and increased levels of the DNA damage marker γH2Ax. EHMT2 normally promotes H3K9 methylation and DDR signaling. Given that inhibition of EHMT2 did not result in extensive proteomic changes, we hypothesized that the tLT-EHMT2 interaction could be involved in DDR pathway deregulation. In the presence of tLT, we report that EHMT2 gained double and single-strand break repair proximal interactors. EHMT2 inhibition rescued proliferation in MCC cells depleted for their T antigens, suggesting impaired DDR and/or lack of cell cycle checkpoint efficiency. Combined tLT and EHMT2 inhibition led to altered DDR signaling, evidenced by multiple alterations in signal transduction. Together, our data strongly suggest that tLT hijacks multiple components of the DNA damage machinery to enhance tolerance to DNA damage in MCC cells which could be at the basis of, the remarkable genetic stability of these cancers.

INSTRUMENT(S): Q Exactive

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Epithelial Cell, Early Embryonic Cell

DISEASE(S): Merkel Cell Carcinoma

SUBMITTER: Kamel Bachiri  

LAB HEAD: Michel Salzet

PROVIDER: PXD044782 | Pride | 2024-06-04

REPOSITORIES: Pride

Dataset's files

Source:
Action DRS
Data_MS_MCC_EHMT2.zip Other
proteinGroupsWaGa_Brd.txt Txt
proteinGroups_EHMT2_BioID.txt Txt
proteinGroups_shRNA.txt Txt
proteinGroups_tLT.txt Txt
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