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The Replisome-Coupled E3 Ubiquitin Ligase Rtt101Mms22 Counteracts Mrc1 Function to Tolerate Genotoxic Stress.

Type of publication Peer-reviewed
Publikationsform Original article (peer-reviewed)
Author Buser Raymond, Kellner Vanessa, Melnik Andre, Wilson-Zbinden Caroline, Schellhaas René, Kastner Lisa, Piwko Wojciech, Dees Martina, Picotti Paola, Maric Marija, Labib Karim, Luke Brian, Peter Matthias,
Project ER-phagy mechanisms to maintain and restore endoplasmic reticulum homeostasis
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Original article (peer-reviewed)

Journal PLoS genetics
Volume (Issue) 12(2)
Page(s) 1005843 - 1005843
Title of proceedings PLoS genetics
DOI 10.1371/journal.pgen.1005843

Open Access

URL https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4743919/
Type of Open Access Publisher (Gold Open Access)

Abstract

Faithful DNA replication and repair requires the activity of cullin 4-based E3 ubiquitin ligases (CRL4), but the underlying mechanisms remain poorly understood. The budding yeast Cul4 homologue, Rtt101, in complex with the linker Mms1 and the putative substrate adaptor Mms22 promotes progression of replication forks through damaged DNA. Here we characterized the interactome of Mms22 and found that the Rtt101(Mms22) ligase associates with the replisome progression complex during S-phase via the amino-terminal WD40 domain of Ctf4. Moreover, genetic screening for suppressors of the genotoxic sensitivity of rtt101Δ cells identified a cluster of replication proteins, among them a component of the fork protection complex, Mrc1. In contrast to rtt101Δ and mms22Δ cells, mrc1Δ rtt101Δ and mrc1Δ mms22Δ double mutants complete DNA replication upon replication stress by facilitating the repair/restart of stalled replication forks using a Rad52-dependent mechanism. Our results suggest that the Rtt101(Mms22) E3 ligase does not induce Mrc1 degradation, but specifically counteracts Mrc1's replicative function, possibly by modulating its interaction with the CMG (Cdc45-MCM-GINS) complex at stalled forks.
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