Stemness factor Sall4 is required for DNA damage response in embryonic stem cells

Jianhua Xiong; Dilyana Todorova; Ning-Yuan Su; Jinchul Kim; Pei-Jen Lee; Zhouxin Shen; Steven P Briggs; Yang Xu

doi:10.1083/jcb.201408106

Stemness factor Sall4 is required for DNA damage response in embryonic stem cells

J Cell Biol. 2015 Mar 2;208(5):513-20. doi: 10.1083/jcb.201408106.

Authors

Jianhua Xiong¹, Dilyana Todorova¹, Ning-Yuan Su¹, Jinchul Kim², Pei-Jen Lee¹, Zhouxin Shen¹, Steven P Briggs¹, Yang Xu³

Affiliations

¹ Section of Molecular Biology and Section of Cell and Developmental Biology, Division of Biological Sciences, University of California, San Diego, La Jolla, CA 92093.
² 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.
³ 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.

Abstract

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

ATP-Binding Cassette Transporters / genetics
ATP-Binding Cassette Transporters / metabolism
Acid Anhydride Hydrolases
Animals
Ataxia Telangiectasia Mutated Proteins / genetics
Ataxia Telangiectasia Mutated Proteins / metabolism
Cell Cycle Proteins / genetics
Cell Cycle Proteins / metabolism
Chromosomal Proteins, Non-Histone / genetics
Chromosomal Proteins, Non-Histone / metabolism
DNA Breaks, Double-Stranded*
DNA Repair Enzymes / genetics
DNA Repair Enzymes / metabolism
DNA-Binding Proteins / genetics
DNA-Binding Proteins / metabolism*
Embryonic Stem Cells / cytology
Embryonic Stem Cells / metabolism*
MRE11 Homologue Protein
Mice
Mice, Knockout
Nuclear Proteins / genetics
Nuclear Proteins / metabolism
Transcription Factors / genetics
Transcription Factors / metabolism*

Substances

ATP-Binding Cassette Transporters
Cell Cycle Proteins
Chromosomal Proteins, Non-Histone
DNA-Binding Proteins
Mre11a protein, mouse
Nijmegen breakage syndrome 1 protein, mouse
Nuclear Proteins
SWI-SNF-B chromatin-remodeling complex
Sall4 protein, mouse
Smarcd1 protein, mouse
Transcription Factors
Ataxia Telangiectasia Mutated Proteins
Atm protein, mouse
MRE11 Homologue Protein
Acid Anhydride Hydrolases
Rad50 protein, mouse
DNA Repair Enzymes