title: The ubiquitin E3 ligase Rtt101 affects the replication stress response and replicative senescence through Mrc1/Claspin
creator: Kastner, Lisa
subject: ddc-500
subject: 500 Natural sciences and mathematics
subject: ddc-570
subject: 570 Life sciences
description: Budding yeast cells deficient of the ubiquitin E3 ligase Rtt101 are highly sensitive to the genotoxic agents MMS and CPT, which cause DNA damage that leads to replication fork stalling in the ensuing S-phase. In a genetic screen we identified the replisome component Mrc1 as a key suppressor of rtt101 drug sensitivity. The rescue of rtt101 cells by MRC1 deletion depended on Rad52. The loss of Mrc's checkoint function was not sufficient to alleviate rtt101 drug sensitivity. Instead, the replicative function of Mrc1 seemed tobe toxic for rtt101 cells. We propose that the ubiquitination of Mrc1 (or an unknown factor regulating Mrc1) by Rtt101 modulates the replisome at the stalled fork, possibly inducing the uncoupling of the helicase from the polymerase. This could allow the production of ssDNA that might trigger replication fork repair or restart by a homologous recombination-based pathway.   Telomere shortening is a natural process during replicative senescence. We could show that Rtt101 prevents premature senescence without affecting telomere length. Our results indicate that Rtt101 and Mrc1 protect shortening telomeres through a common mechanism. We speculate that Rtt101 and Mrc1 act in concert to prevent precocious senescence signalling by delaying the creation of subtelomeric ssDNA.  Thus this study provides insights into how the Rtt101 ubiquitin E3 ligase functions to promote genome stability in the face of replication stress and replicative senescence.
date: 2016
type: Dissertation
type: info:eu-repo/semantics/doctoralThesis
type: NonPeerReviewed
format: application/pdf
identifier: https://archiv.ub.uni-heidelberg.de/volltextserverhttps://archiv.ub.uni-heidelberg.de/volltextserver/21406/1/thesis%20Lisa%20Kastner%20submitted%2014.04.2016.pdf
identifier: DOI:10.11588/heidok.00021406
identifier: urn:nbn:de:bsz:16-heidok-214064
identifier:   Kastner, Lisa  (2016) The ubiquitin E3 ligase Rtt101 affects the replication stress response and replicative senescence through Mrc1/Claspin.  [Dissertation]     
relation: https://archiv.ub.uni-heidelberg.de/volltextserver/21406/
rights: info:eu-repo/semantics/openAccess
rights: http://archiv.ub.uni-heidelberg.de/volltextserver/help/license_urhg.html
language: eng