title: Regulation of DNA damage responses and cell cycle progression by hMOB2.
abstract: Mps one binder proteins (MOBs) are conserved regulators of essential signalling pathways. Biochemically, human MOB2 (hMOB2) can inhibit NDR kinases by competing with hMOB1 for binding to NDRs. However, biological roles of hMOB2 have remained enigmatic. Here, we describe novel functions of hMOB2 in the DNA damage response (DDR) and cell cycle regulation. hMOB2 promotes DDR signalling, cell survival and cell cycle arrest after exogenously induced DNA damage. Under normal growth conditions in the absence of exogenously induced DNA damage hMOB2 plays a role in preventing the accumulation of endogenous DNA damage and a subsequent p53/p21-dependent G1/S cell cycle arrest. Unexpectedly, these molecular and cellular phenotypes are not observed upon NDR manipulations, indicating that hMOB2 performs these functions independent of NDR signalling. Thus, to gain mechanistic insight, we screened for novel binding partners of hMOB2, revealing that hMOB2 interacts with RAD50, facilitating the recruitment of the MRE11-RAD50-NBS1 (MRN) DNA damage sensor complex and activated ATM to DNA damaged chromatin. Taken together, we conclude that hMOB2 supports the DDR and cell cycle progression.
authors.affiliation: UCL Cancer Institute, University College London, WC1E 6BT, London, United Kingdom.
authors.forename: Valenti
authors.initials: V
authors.lastname: Gomez
authors.affiliation: UCL Cancer Institute, University College London, WC1E 6BT, London, United Kingdom.
authors.forename: Ramazan
authors.initials: R
authors.lastname: Gundogdu
authors.affiliation: UCL Cancer Institute, University College London, WC1E 6BT, London, United Kingdom.
authors.forename: Marta
authors.initials: M
authors.lastname: Gomez
authors.affiliation: UCL Cancer Institute, University College London, WC1E 6BT, London, United Kingdom.
authors.forename: Lily
authors.initials: L
authors.lastname: Hoa
authors.affiliation: UCL Cancer Institute, University College London, WC1E 6BT, London, United Kingdom.
authors.forename: Neelam
authors.initials: N
authors.lastname: Panchal
authors.affiliation: Genome Damage and Stability Centre, University of Sussex, BN1 9RH, Brighton, United Kingdom.
authors.forename: Mark
authors.initials: M
authors.lastname: O'Driscoll
authors.affiliation: UCL Cancer Institute, University College London, WC1E 6BT, London, United Kingdom. Electronic address: a.hergovich@ucl.ac.uk.
authors.forename: Alexander
authors.initials: A
authors.lastname: Hergovich
mesh_terms: D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D064007:Ataxia Telangiectasia Mutated Proteins / Q000378:metabolism; D019556:COS Cells; D018797:Cell Cycle Proteins / Q000378:metabolism; D045744:Cell Line, Tumor; D002522:Chlorocebus aethiops; D002868:Chromosomal Proteins, Non-Histone / Q000378:metabolism; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D004249:DNA Damage; D004317:Doxorubicin / Q000494:pharmacology; D059585:G1 Phase Cell Cycle Checkpoints / Q000187:drug effects / Q000528:radiation effects; D006801:Humans; D009419:Nerve Tissue Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D009687:Nuclear Proteins / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects / Q000528:radiation effects; D034741:RNA, Small Interfering / Q000378:metabolism; D011839:Radiation, Ionizing; D059807:S Phase Cell Cycle Checkpoints / Q000187:drug effects / Q000528:radiation effects; D015398:Signal Transduction / Q000187:drug effects / Q000528:radiation effects; D016159:Tumor Suppressor Protein p53 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D000098550:Structural Maintenance of Chromosome Protein 1
chemical_list: D000903:Antibiotics, Antineoplastic; D018797:Cell Cycle Proteins; D002868:Chromosomal Proteins, Non-Histone; D050759:Cyclin-Dependent Kinase Inhibitor p21; C431903:MOB2 protein, human; C112156:NBN protein, human; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D034741:RNA, Small Interfering; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D000098550:Structural Maintenance of Chromosome Protein 1; D004317:Doxorubicin; D064007:Ataxia Telangiectasia Mutated Proteins
keywords: Cell cycle checkpoint activation; Cell cycle progression; DNA damage response signalling; MRE11–RAD50–NBS1 protein complex; Mps one binder 2; p53 tumour suppressor protein