title: Chromosome territory relocation during DNA repair requires nuclear myosin 1 recruitment to chromatin mediated by ϒ-H2AX signaling.
abstract: During DNA damage response (DDR), certain gene rich chromosome territories (CTs) relocate to newer positions within interphase nuclei and revert to their native locations following repair. Such dynamic relocation of CTs has been observed under various cellular conditions, however, the underlying mechanistic basis of the same has remained largely elusive. In this study, we aim to understand the temporal and molecular details of such crosstalk between DDR signaling and CT relocation dynamics. We demonstrate that signaling at DNA double strand breaks (DSBs) by the phosphorylated histone variant (ϒ-H2AX) is a pre-requisite for damage induced CT relocation, as cells deficient in ϒ-H2AX signaling fail to exhibit such a response. Inhibition of Rad51 or DNA Ligase IV mediated late steps of double strand break repair does not seem to abrogate CT relocation completely. Upon DNA damage, an increase in the levels of chromatin bound motor protein nuclear myosin 1 (NM1) ensues, which appears to be functionally linked to ϒ-H2AX signaling. Importantly, the motor function of NM1 is essential for its recruitment to chromatin and CT relocation following damage. Taking these observations together, we propose that early DDR sensing and signaling result in NM1 recruitment to chromosomes which in turn guides DNA damage induced CT relocation.
authors.affiliation: Department of Biological Sciences, Tata Institute of Fundamental Research, Mumbai, Maharashtra 400005, India.
authors.forename: Mugdha
authors.initials: M
authors.lastname: Kulashreshtha
authors.affiliation: Department of Biological Sciences, Tata Institute of Fundamental Research, Mumbai, Maharashtra 400005, India UM-DAE Centre for Excellence in Basic Sciences, Biological Sciences, Kalina Campus, Santacruz (E), Mumbai, Maharashtra 400098, India.
authors.forename: Ishita S
authors.initials: IS
authors.lastname: Mehta
authors.affiliation: Department of Biological Sciences, Tata Institute of Fundamental Research, Mumbai, Maharashtra 400005, India UM-DAE Centre for Excellence in Basic Sciences, Biological Sciences, Kalina Campus, Santacruz (E), Mumbai, Maharashtra 400098, India.
authors.forename: Pradeep
authors.initials: P
authors.lastname: Kumar
authors.affiliation: Department of Biological Sciences, Tata Institute of Fundamental Research, Mumbai, Maharashtra 400005, India bjrao@tifr.res.in.
authors.forename: Basuthkar J
authors.initials: BJ
authors.lastname: Rao
mesh_terms: D055162:Biocatalysis; D002843:Chromatin / Q000378:metabolism*; D002877:Chromosomes, Human / Q000378:metabolism*; D004249:DNA Damage; D000072481:DNA Ligase ATP / Q000378:metabolism; D004260:DNA Repair; D005347:Fibroblasts / Q000378:metabolism; D006657:Histones / Q000378:metabolism*; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D050505:Mutant Proteins / Q000378:metabolism; D024461:Myosin Type I / Q000378:metabolism*; D010766:Phosphorylation; D051135:Rad51 Recombinase / Q000378:metabolism; D015398:Signal Transduction; D014162:Transfection
chemical_list: D002843:Chromatin; C468783:H2AX protein, human; D006657:Histones; D050505:Mutant Proteins; D051135:Rad51 Recombinase; D024461:Myosin Type I; C460367:MYO1C protein, human; D000072481:DNA Ligase ATP