title: Chaperoning HMGA2 protein protects stalled replication forks in stem and cancer cells.
abstract: Maintaining genome integrity requires the accurate and complete replication of chromosomal DNA. This is of the utmost importance for embryonic stem cells (ESCs), which differentiate into cells of all lineages, including germ cells. However, endogenous and exogenous factors frequently induce stalling of replication forks in every cell cycle, which can trigger mutations and chromosomal instabilities. We show here that the oncofetal, nonhistone chromatin factor HMGA2 equips cells with a highly effective first-line defense mechanism against endonucleolytic collapse of stalled forks. This fork-stabilizing function most likely employs scaffold formation at branched DNA via multiple DNA-binding domains. Moreover, HMGA2 works independently of other human factors in two heterologous cell systems to prevent DNA strand breaks. This fork chaperone function seemingly evolved to preserve ESC genome integrity. It is hijacked by tumor (stem) cells to also guard their genomes against DNA-damaging agents widely used to treat cancer patients.
authors: School of Biological Sciences, Nanyang Technological University, 60 Nanyang Drive, Singapore 637551, Singapore.
authors: Haojie
authors: H
authors: Yu
authors: Institute of Molecular and Cell Biology, Proteos, 61 Biopolis Drive, Singapore 138673, Singapore; Bioprocessing Technology Institute, 20 Biopolis Way, 6-01 Centros, Singapore 138668, Singapore.
authors: Hong Hwa
authors: HH
authors: Lim
authors: Division of Biomedical Sciences, The Herman Ostrow School of Dentistry of the University of Southern California, Los Angeles, CA 90089, USA.
authors: Natalia O
authors: NO
authors: Tjokro
authors: School of Biological Sciences, Nanyang Technological University, 60 Nanyang Drive, Singapore 637551, Singapore.
authors: Padmapriya
authors: P
authors: Sathiyanathan
authors: Department of Human Anatomy and Cell Science, Faculty of Medicine, University of Manitoba, Winnipeg, MB R3E 0J9, Canada.
authors: Suchitra
authors: S
authors: Natarajan
authors: Institute of Molecular and Cell Biology, Proteos, 61 Biopolis Drive, Singapore 138673, Singapore.
authors: Tian Wei
authors: TW
authors: Chew
authors: Department of Human Anatomy and Cell Science, Faculty of Medicine, University of Manitoba, Winnipeg, MB R3E 0J9, Canada; Department of Medical Microbiology and Infectious Diseases, Faculty of Medicine, University of Manitoba, Winnipeg, MB R3E 0J9, Canada; Department of Surgery, Faculty of Medicine, University of Manitoba, Winnipeg, MB R3E 0J9, Canada.
authors: Thomas
authors: T
authors: Klonisch
authors: Division of Biomedical Sciences, The Herman Ostrow School of Dentistry of the University of Southern California, Los Angeles, CA 90089, USA.
authors: Steven D
authors: SD
authors: Goodman
authors: Institute of Molecular and Cell Biology, Proteos, 61 Biopolis Drive, Singapore 138673, Singapore.
authors: Uttam
authors: U
authors: Surana
authors: School of Biological Sciences, Nanyang Technological University, 60 Nanyang Drive, Singapore 637551, Singapore. Electronic address: pdroge@ntu.edu.sg.
authors: Peter
authors: P
authors: Dröge
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D053903:DNA Breaks, Double-Stranded; D004261:DNA Replication; D053595:Embryonic Stem Cells / Q000378:metabolism*; D042822:Genomic Instability; D025743:HMGA2 Protein / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D051379:Mice; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism*
chemical_list: D025743:HMGA2 Protein