ATR and ATRIP: Partners in Checkpoint Signaling

The checkpoint kinases ATM (ataxia telangiectasia mutated) and ATR (ATM and Rad3 related) transduce genomic stress signals to halt cell cycle progression and promote DNA repair. We report the identification of an ATR-interacting protein (ATRIP) that is phosphorylated by ATR, regulates ATR expression, and is an essential component of the DNA damage checkpoint pathway. ATR and ATRIP both localize to intranuclear foci after DNA damage or inhibition of replication. Deletion of ATR mediated by the Cre recombinase caused the loss of ATR and ATRIP expression, loss of DNA damage checkpoint responses, and cell death. Therefore, ATR is essential for the viability of human somatic cells. Small interfering RNA directed against ATRIP caused the loss of both ATRIP and ATR expression and the loss of checkpoint responses to DNA damage. Thus, ATRIP and ATR are mutually dependent partners in cell cycle checkpoint signaling pathways.

[1]  Y. Shiloh.  ATM and ATR: networking cellular responses to DNA damage. , 2001, Current opinion in genetics & development.

[2]  A. Carr,et al.  A Rad3–Rad26 complex responds to DNA damage independently of other checkpoint proteins , 1999, Nature Cell Biology.

[3]  S. Elledge,et al.  Recovery from DNA replicational stress is the essential function of the S-phase checkpoint pathway. , 1998, Genes & development.

[4]  G. Lucchini,et al.  The checkpoint protein Ddc2, functionally related to S. pombe Rad26, interacts with Mec1 and is regulated by Mec1-dependent phosphorylation in budding yeast. , 2000, Genes & development.

[5]  S. Schreiber,et al.  cDNA cloning and gene mapping of a candidate human cell cycle checkpoint protein. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[6]  J. Sekelsky,et al.  mus304 encodes a novel DNA damage checkpoint protein required during Drosophila development. , 2000, Genes & development.

[7]  Katsunori Sugimoto,et al.  Pie1, a Protein Interacting with Mec1, Controls Cell Growth and Checkpoint Responses in Saccharomyces cerevisiae , 2001, Molecular and Cellular Biology.

[8]  R Rothstein,et al.  A suppressor of two essential checkpoint genes identifies a novel protein that negatively affects dNTP pools. , 1998, Molecular cell.

[9]  D. Baltimore,et al.  ATR disruption leads to chromosomal fragmentation and early embryonic lethality. , 2000, Genes & development.

[10]  Bo Xu,et al.  Involvement of Brca1 in S-Phase and G2-Phase Checkpoints after Ionizing Irradiation , 2001, Molecular and Cellular Biology.

[11]  D. Durocher,et al.  DNA-PK, ATM and ATR as sensors of DNA damage: variations on a theme? , 2001, Current opinion in cell biology.

[12]  S. Jackson,et al.  LCD1: an essential gene involved in checkpoint control and regulation of the MEC1 signalling pathway in Saccharomyces cerevisiae , 2000, The EMBO journal.