Interaction between human mismatch repair recognition proteins and checkpoint sensor Rad9-Rad1-Hus1 |
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| Authors: | Haibo Bai Amrita Madabushi Xin Guan A-Lien Lu |
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| Affiliation: | 1. Department of Biochemistry and Molecular Biology, University of Maryland, Baltimore, MD 21201, USA;2. Greenebaum Cancer Center, University of Maryland, Baltimore, MD 21201, USA;1. Department of Physiology and Croatian Institute for Brain Research, School of Medicine, University of Zagreb, Zagreb, Croatia;2. Fred Hutchinson Cancer Reaserch Center, Seattle, WA 98109, USA;3. Department of Cell Biology, Microbiology, and Molecular Biology, College of Arts and Sciences, University of South Florida, Tampa, Florida 33620;4. Department of Radiation Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 02115;5. Cytogenetics Core Laboratory, Dana-Farber Cancer Institute, Boston, Massachusetts 02115;1. Department of Pharmaceutical Chemistry, Macromolecule and Vaccine Stabilization Center, University of Kansas, Lawrence, Kansas 66047;2. Division of Infectious Disease, Wadsworth Center, New York State Department of Health, Albany, New York 12208;3. Department of Physics and Optical Science, University of North Carolina at Charlotte, Charlotte, North Carolina 28223;4. Applied Bioinformatics Laboratory, Department of Medicinal Chemistry, University of Kansas, Lawrence, Kansas 66047;5. Department of Molecular Biosciences, Center for Computational Biology, University of Kansas, Lawrence, Kansas 66045;6. Department of Biomedical Sciences, School of Public Health, University at Albany, Albany, New York 12201;1. School of Health Sciences, Purdue University, West Lafayette, Indiana;2. Radiation Oncology, University of Washington, Seattle, Washington;3. Radiation Oncology, University of California–Los Angeles, Los Angeles, California;4. Radiation Oncology, Indiana University School of Medicine, Indianapolis, Indiana;6. Radiology and Imaging Sciences, Indiana University School of Medicine, Indianapolis, Indiana |
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| Abstract: | In eukaryotic cells, the cell cycle checkpoint proteins Rad9, Rad1, and Hus1 form the 9-1-1 complex which is structurally similar to the proliferating cell nuclear antigen (PCNA) sliding clamp. hMSH2/hMSH6 (hMutSα) and hMSH2/hMSH3 (hMutSβ) are the mismatch recognition factors of the mismatch repair pathway. hMutSα has been shown to physically and functionally interact with PCNA. Moreover, DNA methylating agent N-methyl-N′-nitro-N-nitrosoguanidine (MNNG) treatment induces the G2/M cell cycle arrest that is dependent on the presence of hMutSα and hMutLα. In this study, we show that each subunit of the human 9-1-1 complex physically interacts with hMSH2, hMSH3, and hMSH6. The 9-1-1 complex from both humans and Schizosaccharomyces pombe can stimulate hMutSα binding with G/T-containing DNA. Rad9, Rad1, and Hus1 individual subunits can also stimulate the DNA binding activity of hMutSα. Human Rad9 and hMSH6 colocalize to nuclear foci of HeLa cells after exposure to MNNG. However, Rad9 does not form foci in MSH6 defective cells following MNNG treatment. In Rad9 knockdown untreated cells, the majority of the MSH6 is in cytoplasm. Following MNNG treatment, Rad9 knockdown cells has abnormal nuclear morphology and MSH6 is distributed around nuclear envelop. Our findings suggest that the 9-1-1 complex is a component of the mismatch repair involved in MNNG-induced damage response. |
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