Project Details
Projekt
Function of the UBZ-containing ATPase Wrnip1 in DNA replication and damage response
Applicant
Professor Dr. Ivan Dikic
Subject Area
Cell Biology
Term
from 2008 to 2014
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 72189856
Ubiquitin (Ub) and Ubiquitin-like modifiers (Ubls) are among the most diverse moieties covalentiy attached to proteins to maintain homeostasis under normal conditions and during stress such as DNA damage. We have previously shown that multiple proteins involved in the DNA damage response (DDR) - including the Y-family polymerases kappa and eta, Werner helicase (Wrn)-interacting protein 1 (Wmip1), FAN-1 nuclease and Rad18 ubiquitin ligase - contain Ub-binding Zn finger (UBZ) domains that regulate their sub-nuclear localization inside focal structures. Here we propose to study the role of Wrnip1 in DNA replication, telomere maintenance and genome stability. We have found that Wmip1 foci co-localize with heterochromatic regions including centromeres and telomeres and that Wrnip1 interacts with the telomeric protein TRF2 (telomere repeat factor 2) but not TRF1. We have also found that acute Wrnip1 depletion by RNA interference causes chromosomal instability involving both centromeres and telomeres, To dissect the functional role of Wrnip1, we will combine biochemical and cellular methods to study: a) the composition of Wrnip1-associated complexes; b) the dynamics of Wrnip1 foci in living cells under replication stress; c) the relevance of Wrnip1 for telomere maintenance, DNA replication and genome stability; d) the effects of the deletion of WRNIP1 and associated genes such as RAD18 and WRN in defined tissues and organs in genetically-engineered mice models. We expect that these studies will shed light onto the physiological role and mechanism of action of Wrnip1 during DDR.
DFG Programme
Priority Programmes
