title: MKP1 phosphatase mediates G1-specific dephosphorylation of H3Serine10P in response to DNA damage.
abstract: Histone mark, H3S10 phosphorylation plays a dual role in a cell by maintaining relaxed chromatin for active transcription in interphase and condensed chromatin state in mitosis. The level of H3S10P has also been shown to alter on DNA damage; however, its cell cycle specific behavior and regulation during DNA damage response is largely unexplored. In the present study, we demonstrate G1 cell cycle phase specific reversible loss of H3S10P in response to IR-induced DNA damage is mediated by opposing activities of phosphatase, MKP1 and kinase, MSK1 of the MAP kinase pathway. We also show that the MKP1 recruits to the chromatin in response to DNA damage and correlates with the decrease of H3S10P, whereas MKP1 is released from chromatin during recovery phase of DDR. Furthermore, blocking of H3S10 dephosphorylation by MKP1 inhibition impairs DNA repair process and results in poor survival of WRL68 cells. Collectively, our data proposes a pathway regulating G1 cell cycle phase specific reversible reduction of H3S10P on IR induced DNA damage and also raises the possibility of combinatorial modulation of H3S10P with specific inhibitors to target the cancer cells in G1-phase of cell cycle.
authors.affiliation: Epigenetics and Chromatin Biology Group, Gupta Lab, Cancer Research Institute, Advanced Centre for Treatment Research and Education in Cancer (ACTREC), Tata Memorial Centre, Kharghar, Navi Mumbai 410210 MH, India.
authors.forename: Ajit K
authors.initials: AK
authors.lastname: Sharma
authors.affiliation: Epigenetics and Chromatin Biology Group, Gupta Lab, Cancer Research Institute, Advanced Centre for Treatment Research and Education in Cancer (ACTREC), Tata Memorial Centre, Kharghar, Navi Mumbai 410210 MH, India.
authors.forename: Shafqat A
authors.initials: SA
authors.lastname: Khan
authors.affiliation: Epigenetics and Chromatin Biology Group, Gupta Lab, Cancer Research Institute, Advanced Centre for Treatment Research and Education in Cancer (ACTREC), Tata Memorial Centre, Kharghar, Navi Mumbai 410210 MH, India.
authors.forename: Asmita
authors.initials: A
authors.lastname: Sharda
authors.affiliation: Epigenetics and Chromatin Biology Group, Gupta Lab, Cancer Research Institute, Advanced Centre for Treatment Research and Education in Cancer (ACTREC), Tata Memorial Centre, Kharghar, Navi Mumbai 410210 MH, India.
authors.forename: Divya V
authors.initials: DV
authors.lastname: Reddy
authors.affiliation: Epigenetics and Chromatin Biology Group, Gupta Lab, Cancer Research Institute, Advanced Centre for Treatment Research and Education in Cancer (ACTREC), Tata Memorial Centre, Kharghar, Navi Mumbai 410210 MH, India. Electronic address: sgupta@actrec.gov.in.
authors.forename: Sanjay
authors.initials: S
authors.lastname: Gupta
mesh_terms: D053119:Benzophenanthridines / Q000494:pharmacology; D002460:Cell Line; D002843:Chromatin / Q000235:genetics / Q000648:ultrastructure; D003114:Colony-Forming Units Assay; D020552:Comet Assay; D004247:DNA / Q000235:genetics / Q000528:radiation effects; D004249:DNA Damage; D004260:DNA Repair / Q000235:genetics / Q000502:physiology*; D054638:Dual Specificity Phosphatase 1 / Q000037:antagonists & inhibitors / Q000502:physiology*; D016193:G1 Phase / Q000502:physiology*; D005720:Gamma Rays; D006657:Histones / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D006801:Humans; D007546:Isoquinolines / Q000494:pharmacology; D020935:MAP Kinase Signaling System; D009707:Nucleosomes / Q000528:radiation effects; D010766:Phosphorylation; D017354:Point Mutation; D011499:Protein Processing, Post-Translational / Q000502:physiology*; D038744:Ribosomal Protein S6 Kinases, 90-kDa / Q000037:antagonists & inhibitors / Q000502:physiology; D013449:Sulfonamides / Q000494:pharmacology
chemical_list: D053119:Benzophenanthridines; D002843:Chromatin; C468783:H2AX protein, human; D006657:Histones; D007546:Isoquinolines; D009707:Nucleosomes; D013449:Sulfonamides; D004247:DNA; C005705:sanguinarine; D038744:Ribosomal Protein S6 Kinases, 90-kDa; C116919:mitogen and stress-activated protein kinase 1; C517019:DUSP1 protein, human; D054638:Dual Specificity Phosphatase 1; C063509:N-(2-(4-bromocinnamylamino)ethyl)-5-isoquinolinesulfonamide
keywords: Cell cycle; DNA damage response; H3serine10 phosphorylation; Kinases; Phosphatases