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Published online before print February 18, 2008, 10.1101/gad.1627708
GENES & DEVELOPMENT 22:587-600, 2008
©2008 by Cold Spring Harbor Laboratory Press; ISSN 0890-9369/ $5.00
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Cep164 is a mediator protein required for the maintenance of genomic stability through modulation of MDC1, RPA, and CHK1

Sudhakar Sivasubramaniam1, Xuemin Sun, Yen-Ru Pan, Shaohui Wang, and Eva Y.-H.P. Lee2

Department of Biological Chemistry and Department of Developmental and Biology, University of California, Irvine, California 92697, USA

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: DNA damage signal pathways; ATR; CEP164; RPA; MDC1; CHK1; H2AX]]

Received October 22, 2007; revised version accepted January 10, 2008.

1 Present address: Department of Biotechnology, Manonmaniam Sundaranar University, Alwarkurichi, Thirunelveli Dt., Taminlnadu-627412, India.

2 Corresponding author.

E-MAIL elee{at}uci.edu; FAX (949) 824-9767.

Supplemental material is available at http://www.genesdev.org.

Article published online ahead of print. Article and publication date are online at http://www.genesdev.org/cgi/doi/10.1101/gad.1627708.


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