Dataset Information

TAP-MS of human BRAT1 and WDR73

ABSTRACT: Using a combination of proteomics, interaction studies and structural characterization we show that WDR73 and BRAT1 are interactors of the heterodimer INTS9-11 of INT. Both proteins are involved in the stability and formation of the cleavage module of INT consisting of INTS4-9-11.

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human)

SUBMITTER: Kevin Sabath

LAB HEAD: Dr. Stefanie Jonas

PROVIDER: PXD044324 | Pride | 2024-07-31

REPOSITORIES: Pride

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Dataset's files

Source:

			Action	DRS
	20221215_C30318_002_S437293_GFP_1_Control.raw	Raw
	20221215_C30318_004_S437295_GFP_3_Control.raw	Raw
	20221215_C30318_005_S437296_GFP_4_Control.raw	Raw
	20221215_C30318_007_S437297_WDR73_1_Group_1.raw	Raw
	20221215_C30318_009_S437299_WDR73_3_Group_1.raw	Raw

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Publications

Assembly mechanism of Integrator's RNA cleavage module.

Sabath Kevin K Qiu Chunhong C Jonas Stefanie S

Molecular cell 20240719 15

The modular Integrator complex is a transcription regulator that is essential for embryonic development. It attenuates coding gene expression via premature transcription termination and performs 3'-processing of non-coding RNAs. For both activities, Integrator requires endonuclease activity that is harbored by an RNA cleavage module consisting of INTS4-9-11. How correct assembly of Integrator modules is achieved remains unknown. Here, we show that BRAT1 and WDR73 are critical biogenesis factors ...[more]

PMID: 39032489

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Project description:The integrator complex (INT) is an essential regulator of RNA biogenesis across evolution. Most current findings describe INT's function in states of equilibrium, presenting a research gap in INT's role in dynamic states, such as in infections and cancers. Viruses hijack cellular RNA machinery to transcribe their genes and produce viral progeny, presenting a unique condition to investigate INT-dependent RNA regulation under perturbation. Kaposi's sarcoma-associated herpesvirus (KSHV) is an oncogenic DNA virus that causes two deadly cancers, Kaposi's sarcoma and primary effusion lymphoma. KSHV undergoes a highly regulated and robust transcription of viral genes upon lytic reactivation, providing a complex and dynamic system to investigate integrator-mediated viral/host RNA regulation. We find that integrator subunit 11 (INTS11), the enzymatic core of INT, is essential for KSHV lytic replication triggered by reactivation or primary infection. Further RNA-seq analyses revealed a dynamic and unique signature of human transcriptomes during each lytic stage, respectively. Although the knockdown of INTS11 resulted in selective upregulation and downregulation of certain human gene transcription, INTS11's loss globally repressed the KSHV transcriptome throughout KSHV lytic replication. This inhibited viral lytic gene expression, viral genome replication, and virion production. Integrator subunits 9 and 6 are also important for KSHV lytic replication. Mechanistically, ChIP-seq analysis showed that INTS11 is increasingly recruited to the KSHV genome with some unique binding patterns as the lytic cycle progresses, suggesting that KSHV hijacks INTS11 during lytic gene transcriptions. In all, our findings reveal the essential roles of the Integrator complex in KSHV lytic replication.IMPORTANCEThe integrator complex (INT) is essential for RNA metabolism and is fundamental to all organisms, but its function and regulation during viral infection are not well described. Kaposi's sarcoma-associated herpesvirus (KSHV) infection establishes lifelong infection and causes two deadly cancers; however, no vaccine is available. Using KSHV as a model, we found that integrator subunit 11 (INTS11), the enzymatic core of INT, is recruited to the KSHV genome under lytic phases and plays an essential role in facilitating global KSHV lytic mRNA transcription and viral production. This reveals the critical role of INT in viral infection, a common and inevitable event in human life.