A crucial role for bone morphogenetic protein-Smad1 signalling in the DNA damage response

Jenny Fung Ling Chau, Deyong Jia, Zhongfeng Wang, Zhi Liu, Yuanyu Hu, Xin Zhang, Hao Jia, Keng Po Lai, Wai Fook Leong, Bi Jin Au, Yuji Mishina, Ye-Guang Chen, Christine Biondi, Elizabeth Robertson, Dong Xie, Huijuan Liu, Lin He, Xueying Wang, Qiang Yu and Baojie Li ()
Additional contact information
Jenny Fung Ling Chau: The Institute of Molecular and Cell Biology
Deyong Jia: Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders, Ministry of Education, Shanghai Jiao Tong University
Zhongfeng Wang: Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders, Ministry of Education, Shanghai Jiao Tong University
Zhi Liu: The Institute of Molecular and Cell Biology
Yuanyu Hu: The Institute of Molecular and Cell Biology
Xin Zhang: Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders, Ministry of Education, Shanghai Jiao Tong University
Hao Jia: Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders, Ministry of Education, Shanghai Jiao Tong University
Keng Po Lai: The Institute of Molecular and Cell Biology
Wai Fook Leong: The Institute of Molecular and Cell Biology
Bi Jin Au: The Institute of Molecular and Cell Biology
Yuji Mishina: School of Dentistry, University of Michigan
Ye-Guang Chen: Tsinghua University
Christine Biondi: Sir William Dunn School of Pathology, University of Oxford
Elizabeth Robertson: Sir William Dunn School of Pathology, University of Oxford
Dong Xie: Institutes for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences
Huijuan Liu: Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders, Ministry of Education, Shanghai Jiao Tong University
Lin He: Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders, Ministry of Education, Shanghai Jiao Tong University
Xueying Wang: National University of Singapore
Qiang Yu: Genome Institute of Singapore
Baojie Li: Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders, Ministry of Education, Shanghai Jiao Tong University

Nature Communications, 2012, vol. 3, issue 1, 1-11

Abstract: Abstract DNA damage and the elicited cellular response underlie the etiology of tumorigenesis and ageing. Yet, how this response integrates inputs from cells' environmental cues remains underexplored. Here we report that the BMP-Smad1 pathway, which is essential for embryonic development and tissue homeostasis, has an important role in the DNA damage response and oncogenesis. On genotoxic stress, Atm phosphorylates BMPs-activated Smad1 in the nucleus on S239, which disrupts Smad1 interaction with protein phosphatase PPM1A, leading to enhanced activation and upregulation of Smad1. Smad1 then interacts with p53 and inhibits Mdm2-mediated p53 ubiquitination and degradation to regulate cell proliferation and survival. Enhanced Smad1 S239 phosphorylation, and Smad1 mutations causing S239 substitution were detected in oesophageal and gastric cancer samples, respectively. These findings suggest that BMP-Smad1 signalling participates in the DNA damage response via the Atm-p53 pathway, thus providing a molecular mechanism whereby BMP-Smad1 loss-of-function leads to tumorigenesis, for example, juvenile polyposis and Cowden syndromes.

Date: 2012
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DOI: 10.1038/ncomms1832

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