title: p53 Maintains Genomic Stability by Preventing Interference between Transcription and Replication.
abstract: p53 tumor suppressor maintains genomic stability, typically acting through cell-cycle arrest, senescence, and apoptosis. We discovered a function of p53 in preventing conflicts between transcription and replication, independent of its canonical roles. p53 deficiency sensitizes cells to Topoisomerase (Topo) II inhibitors, resulting in DNA damage arising spontaneously during replication. Topoisomerase IIα (TOP2A)-DNA complexes preferentially accumulate in isogenic p53 mutant or knockout cells, reflecting an increased recruitment of TOP2A to regulate DNA topology. We propose that p53 acts to prevent DNA topological stress originating from transcription during the S phase and, therefore, promotes normal replication fork progression. Consequently, replication fork progression is impaired in the absence of p53, which is reversed by transcription inhibition. Pharmacologic inhibition of transcription also attenuates DNA damage and decreases Topo-II-DNA complexes, restoring cell viability in p53-deficient cells. Together, our results demonstrate a function of p53 that may underlie its role in tumor suppression.
authors.affiliation: IFOM-p53Lab Joint Research Laboratory, Agency for Science, Technology and Research, Singapore 138648, Singapore.
authors.forename: Constance Qiao Xin
authors.initials: CQX
authors.lastname: Yeo
authors.affiliation: IFOM-p53Lab Joint Research Laboratory, Agency for Science, Technology and Research, Singapore 138648, Singapore; IFOM, FIRC Institute of Molecular Oncology, 20139 Milan, Italy.
authors.forename: Irina
authors.initials: I
authors.lastname: Alexander
authors.affiliation: IFOM-p53Lab Joint Research Laboratory, Agency for Science, Technology and Research, Singapore 138648, Singapore.
authors.forename: Zhaoru
authors.initials: Z
authors.lastname: Lin
authors.affiliation: IFOM-p53Lab Joint Research Laboratory, Agency for Science, Technology and Research, Singapore 138648, Singapore.
authors.forename: Shuhui
authors.initials: S
authors.lastname: Lim
authors.affiliation: IFOM-p53Lab Joint Research Laboratory, Agency for Science, Technology and Research, Singapore 138648, Singapore.
authors.forename: Obed Akwasi
authors.initials: OA
authors.lastname: Aning
authors.affiliation: IFOM-p53Lab Joint Research Laboratory, Agency for Science, Technology and Research, Singapore 138648, Singapore; IFOM, FIRC Institute of Molecular Oncology, 20139 Milan, Italy.
authors.forename: Ramesh
authors.initials: R
authors.lastname: Kumar
authors.affiliation: Experimental Therapeutics Center, Agency for Science, Technology and Research, Singapore 138669, Singapore.
authors.forename: Kanda
authors.initials: K
authors.lastname: Sangthongpitag
authors.affiliation: Experimental Therapeutics Center, Agency for Science, Technology and Research, Singapore 138669, Singapore.
authors.forename: Vishal
authors.initials: V
authors.lastname: Pendharkar
authors.affiliation: Molecular Engineering Laboratory, Agency for Science, Technology and Research, Singapore 138673, Singapore.
authors.forename: Vincent H B
authors.initials: VHB
authors.lastname: Ho
authors.affiliation: IFOM-p53Lab Joint Research Laboratory, Agency for Science, Technology and Research, Singapore 138648, Singapore; IFOM, FIRC Institute of Molecular Oncology, 20139 Milan, Italy; Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore 117597, Singapore; Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore 308232, Singapore. Electronic address: cfcheok@jrl.a-star.edu.sg.
authors.forename: Chit Fang
authors.initials: CF
authors.lastname: Cheok
mesh_terms: D000951:Antigens, Neoplasm / Q000378:metabolism; D004261:DNA Replication; D004250:DNA Topoisomerases, Type II / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D042822:Genomic Instability; D045325:HCT116 Cells; D006801:Humans; D000075223:Poly-ADP-Ribose Binding Proteins; D059003:Topoisomerase Inhibitors / Q000494:pharmacology; D014158:Transcription, Genetic; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*
chemical_list: D000951:Antigens, Neoplasm; D004268:DNA-Binding Proteins; D000075223:Poly-ADP-Ribose Binding Proteins; D059003:Topoisomerase Inhibitors; D016159:Tumor Suppressor Protein p53; D004250:DNA Topoisomerases, Type II; C000618811:TOP2A protein, human