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Cell. 2013 Aug 29;154(5):983-995. doi: 10.1016/j.cell.2013.07.028.

Proteasome-mediated processing of Def1, a critical step in the cellular response to transcription stress.

Author information

1
Mechanisms of Transcription Laboratory, Clare Hall Laboratories, Cancer Research UK London Research Institute, South Mimms EN6 3LD, UK.
2
Molecular Biology Programme, Memorial Sloan-Kettering Cancer Center, York Avenue 1275, New York, NY 10021, USA.
3
Mechanisms of Transcription Laboratory, Clare Hall Laboratories, Cancer Research UK London Research Institute, South Mimms EN6 3LD, UK. Electronic address: j.svejstrup@cancer.org.uk.

Abstract

DNA damage triggers polyubiquitylation and degradation of the largest subunit of RNA polymerase II (RNAPII), a "mechanism of last resort" employed during transcription stress. In yeast, this process is dependent on Def1 through a previously unresolved mechanism. Here, we report that Def1 becomes activated through ubiquitylation- and proteasome-dependent processing. Def1 processing results in the removal of a domain promoting cytoplasmic localization, resulting in nuclear accumulation of the clipped protein. Nuclear Def1 then binds RNAPII, utilizing a ubiquitin-binding domain to recruit the Elongin-Cullin E3 ligase complex via a ubiquitin-homology domain in the Ela1 protein. This facilitates polyubiquitylation of Rpb1, triggering its proteasome-mediated degradation. Together, these results outline the multistep mechanism of Rpb1 polyubiquitylation triggered by transcription stress and uncover the key role played by Def1 as a facilitator of Elongin-Cullin ubiquitin ligase function.

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PMID:
23993092
PMCID:
PMC3778974
DOI:
10.1016/j.cell.2013.07.028
[Indexed for MEDLINE]
Free PMC Article

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