Stemness factor Sall4 is required for DNA damage response in embryonic stem cells.
Mouse embryonic stem cells (ESCs) are genetically more stable than somatic cells, thereby preventing the passage of genomic abnormalities to their derivatives including germ cells. The underlying mechanisms, however, remain largely unclear. In this paper, we show that the stemness factor Sall4 is required for activating the critical Ataxia Telangiectasia Mutated (ATM)-dependent cellular responses to DNA double-stranded breaks (DSBs) in mouse ESCs and confer their resistance to DSB-induced cytotoxicity. Sall4 is rapidly mobilized to the sites of DSBs after DNA damage. Furthermore, Sall4 interacts with Rad50 and stabilizes the Mre11-Rad50-Nbs1 complex for the efficient recruitment and activation of ATM. Sall4 also interacts with Baf60a, a member of the SWI/SNF (switch/sucrose nonfermentable) ATP-dependent chromatin-remodeling complex, which is responsible for recruiting Sall4 to the site of DNA DSB damage. Our findings provide novel mechanisms to coordinate stemness of ESCs with DNA damage response, ensuring genomic stability during the expansion of ESCs.
Section of Molecular Biology and Section of Cell and Developmental Biology, Division of Biological Sciences, University of California, San Diego, La Jolla, CA 92093.
Jianhua
J
Xiong
Section of Molecular Biology and Section of Cell and Developmental Biology, Division of Biological Sciences, University of California, San Diego, La Jolla, CA 92093.
Dilyana
D
Todorova
Section of Molecular Biology and Section of Cell and Developmental Biology, Division of Biological Sciences, University of California, San Diego, La Jolla, CA 92093.
Ning-Yuan
NY
Su
Section of Molecular Biology and Section of Cell and Developmental Biology, Division of Biological Sciences, University of California, San Diego, La Jolla, CA 92093 Cancer Research Institute, Southern Medical University, Guangzhou 510515, Guangdong, China.
Jinchul
J
Kim
Section of Molecular Biology and Section of Cell and Developmental Biology, Division of Biological Sciences, University of California, San Diego, La Jolla, CA 92093.
Pei-Jen
PJ
Lee
Section of Molecular Biology and Section of Cell and Developmental Biology, Division of Biological Sciences, University of California, San Diego, La Jolla, CA 92093.
Zhouxin
Z
Shen
Section of Molecular Biology and Section of Cell and Developmental Biology, Division of Biological Sciences, University of California, San Diego, La Jolla, CA 92093.
Steven P
SP
Briggs
Section of Molecular Biology and Section of Cell and Developmental Biology, Division of Biological Sciences, University of California, San Diego, La Jolla, CA 92093 yangxu@ucsd.edu.
Yang
Y
Xu
D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000378:metabolism; D017766:Acid Anhydride Hydrolases; D000818:Animals; D064007:Ataxia Telangiectasia Mutated Proteins / Q000235:genetics / Q000378:metabolism; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism; D002868:Chromosomal Proteins, Non-Histone / Q000235:genetics / Q000378:metabolism; D053903:DNA Breaks, Double-Stranded; D045643:DNA Repair Enzymes / Q000235:genetics / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D053595:Embryonic Stem Cells / Q000166:cytology / Q000378:metabolism*; D000076228:MRE11 Homologue Protein; D051379:Mice; D018345:Mice, Knockout; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*
D018528:ATP-Binding Cassette Transporters; D018797:Cell Cycle Proteins; D002868:Chromosomal Proteins, Non-Histone; D004268:DNA-Binding Proteins; C512689:Mre11a protein, mouse; C466108:Nijmegen breakage syndrome 1 protein, mouse; D009687:Nuclear Proteins; C445179:SWI-SNF-B chromatin-remodeling complex; C509167:Sall4 protein, mouse; C529549:Smarcd1 protein, mouse; D014157:Transcription Factors; D064007:Ataxia Telangiectasia Mutated Proteins; C576325:Atm protein, mouse; D000076228:MRE11 Homologue Protein; D017766:Acid Anhydride Hydrolases; C495198:Rad50 protein, mouse; D045643:DNA Repair Enzymes