.gif?ad=15653&adview=true)
Minichromosome maintenance proteins are direct targets of the ATM and ATR checkpoint kinases
- *Department of Biochemistry, Vanderbilt University, Nashville, TN 37232; and ‡Department of Genetics, Center for Genetics and Genomics, and Howard Hughes Medical Institute, Harvard University Medical School, Boston, MA 02115
-
Contributed by Stephen J. Elledge, May 13, 2004
Abstract
The minichromosome maintenance (MCM) 2-7 helicase complex functions to initiate and elongate replication forks. Cell cycle checkpoint signaling pathways regulate DNA replication to maintain genomic stability. We describe four lines of evidence that ATM/ATR-dependent (ataxia-telangiectasia-mutated/ATM- and Rad3-related) checkpoint pathways are directly linked to three members of the MCM complex. First, ATM phosphorylates MCM3 on S535 in response to ionizing radiation. Second, ATR phosphorylates MCM2 on S108 in response to multiple forms of DNA damage and stalling of replication forks. Third, ATR-interacting protein (ATRIP)-ATR interacts with MCM7. Fourth, reducing the amount of MCM7 in cells disrupts checkpoint signaling and causes an intra-S-phase checkpoint defect. Thus, the MCM complex is a platform for multiple DNA damage-dependent regulatory signals that control DNA replication.
Footnotes
-
↵ †To whom correspondence may be addressed at: Department of Biochemistry, Vanderbilt University, 613 Light Hall, Nashville, TN 37232. E-mail: david.cortez{at}vanderbilt.edu. §To whom correspondence may be addressed at: Department of Genetics, Center for Genetics and Genomics, Howard Hughes Medical Institute, Room 158D, New Research Building, Harvard Medical School, 77 Avenue Louis Pasteur, Boston, MA 02115. E-mail: selledge{at}genetics.med.harvard.edu.
-
Abbreviations: ATM, ataxia-telangiectasia-mutated; ATR, ATM- and Rad3-related; HEK, human embryonic kidney; HA, hemagglutinin; HU, hydroxyurea; IR, ionizing radiation; MCM, minichromosome maintenance; P-S, phosphoserine; siRNA, small interfering RNA; SQ2, serine/glutamine 2.
- Copyright © 2004, The National Academy of Sciences
