Cep164 is a mediator protein required for the maintenance of genomic stability through modulation of MDC1, RPA, and CHK1
- 18 February 2008
- journal article
- Published by Cold Spring Harbor Laboratory in Genes & Development
- Vol. 22 (5), 587-600
- https://doi.org/10.1101/gad.1627708
Abstract
The activation of the ataxia telangiectasia mutated (ATM) and ATM/Rad3-related (ATR) kinases triggers a diverse cellular response including the initiation of DNA damage-induced cell cycle checkpoints. Mediator of DNA Damage Checkpoint protein, MDC1, and H2AX are chromatin remodeling factors required for the recruitment of DNA repair proteins to the DNA damage sites. We identified a novel mediator protein, Cep164 (KIAA1052), that interacts with both ATR and ATM. Cep164 is phosphorylated upon replication stress, ultraviolet radiation (UV), and ionizing radiation (IR). Ser186 of Cep164 is phosphorylated by ATR/ATM in vitro and in vivo. The phosphorylation of Ser186 is not affected by RPA knockdown but is severely hampered by MDC1 knockdown. siRNA-mediated silencing of Cep164 significantly reduces DNA damage-induced phosphorylation of RPA, H2AX, MDC1, CHK2, and CHK1, but not NBS1. Analyses of Cep164 knockdown cells demonstrate a critical role of Cep164 in G2/M checkpoint and nuclear divisions. These findings reveal that Cep164 is a key player in the DNA damage-activated signaling cascade.Keywords
This publication has 68 references indexed in Scilit:
- RNF8 Transduces the DNA-Damage Signal via Histone Ubiquitylation and Checkpoint Protein AssemblyCell, 2007
- Cep164, a novel centriole appendage protein required for primary cilium formationThe Journal of cell biology, 2007
- ATR-dependent phosphorylation and activation of ATM in response to UV treatment or replication fork stallingThe EMBO Journal, 2006
- Opposing effects of the UV lesion repair protein XPA and UV bypass polymerase η on ATR checkpoint signalingThe EMBO Journal, 2006
- ATRIP Oligomerization Is Required for ATR-dependent Checkpoint SignalingJournal of Biological Chemistry, 2005
- Probing the chromosome 9p21 region susceptible to DNA double-strand breaks in human cells in vivo by restriction enzyme transferOncogene, 2005
- Replication protein A and γ-H2AX foci assembly is triggered by cellular response to DNA double-strand breaksExperimental Cell Research, 2004
- Proteomic characterization of the human centrosome by protein correlation profilingNature, 2003
- Control of DNA Replication and Chromosome Ploidy by Geminin and Cyclin AMolecular and Cellular Biology, 2002
- Construction by gene targeting in human cells of a ‘conditional’ CDC2 mutant that rereplicates its DNANature Genetics, 1997