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A role for the Trim33 ubiquitin ligase in cellular response to replicative stress

ABSTRACT: Deregulation of RNA polymerase II (RNAPII) by oncoproteins, such as transcription factor Myc, interferes with DNA replication and is a major source of DNA damage and genomic instability. Ubiquitination is a key pathway controlling RNAPII activity via modification of RNAPII subunits or associated regulatory proteins. We uncover a mechanism for genome maintenance by ubiquitin ligase Trim33 and transcription factor E2f4. We show that Trim33 promotes E2f4 protein turnover, restricting interactions of E2f4 with chromatin and with the Recql DNA helicase. Replicative stress blunts Trim33-dependent regulation, which stimulates E2f4 and Recql recruitment to chromatin and facilitates recovery of DNA replication. Deletion of Trim33 triggers chronic recruitment of Recql to chromatin and accelerates DNA replication under stress, accompanied by compromised DDR signaling and DNA repair. Depletion of Trim33 in Myc-overexpressing cells leads to accumulation of replication-associated DNA damage and delays Myc-driven tumorigenesis. We propose that the Trim33-E2f4-Recql axis provides a mechanism to control DNA replication at transcriptionally active chromatin to maintain genome integrity.

INSTRUMENT(S): Orbitrap Fusion

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Epithelial Cell

DISEASE(S): Disease Free

SUBMITTER: Mohamed Ali Jarboui

LAB HEAD: Mohamed Ali Jarboui

PROVIDER: PXD037854 | Pride | 2023-07-24

REPOSITORIES: Pride

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			Action	DRS
	FKL3236-S02-A-10_E2F4_T33KO_IP_1.raw	Raw
	FKL3236-S03-A-11_E2F4_T33KO_IP_2.raw	Raw
	FKL3236-S04-A-12_E2F4_T33KO_IP_3.raw	Raw
	FKL3236-S07-A-7_Ctrl_IgG_IP_1.raw	Raw
	FKL3236-S08-A-8_Ctrl_IgG_IP_2.raw	Raw

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