Imperial College London

DrRobertMahen

Faculty of Natural SciencesDepartment of Physics

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r.mahen

 
 
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Blackett LaboratorySouth Kensington Campus

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Summary

 

Publications

Publication Type
Year
to

20 results found

Nicolai S, Mahen R, Raschella G, Marini A, Pieraccioli M, Malewicz M, Venkitaraman AR, Melino Get al., 2020, ZNF281 is recruited on DNA breaks to facilitate DNA repair by non-homologous end joining, ONCOGENE, Vol: 39, Pages: 754-766, ISSN: 0950-9232

Journal article

Mahen R, Schulte R, 2019, Cell-cell Fusion of Genome Edited Cell Lines for Perturbation of Cellular Structure and Function, JOVE-JOURNAL OF VISUALIZED EXPERIMENTS, ISSN: 1940-087X

Journal article

Sharma P, Mahen R, Rossmann M, Stokes JE, Hardwick B, Huggins DJ, Emery A, Kunciw DL, Hyvonen M, Spring DR, McKenzie GJ, Venkitaraman ARet al., 2019, A cryptic hydrophobic pocket in the polo-box domain of the polo-like kinase PLK1 regulates substrate recognition and mitotic chromosome segregation, SCIENTIFIC REPORTS, Vol: 9, ISSN: 2045-2322

Journal article

Mahen RWJ, 2018, Stable centrosomal roots disentangle to allow interphase centriole independence, PLoS Biology, Vol: 16, ISSN: 1544-9173

The centrosome is a non-membrane bound cellular compartment consisting of two centrioles surrounded by a proteincoat termed the pericentriolar material (PCM). Centrioles generally remain physically associated together (a phenomenoncalled centrosome cohesion), yet how this occurs in the absence of a bounding lipid membrane is unclear. One modelposits that pericentriolar fibres formed from rootletin protein directly link centrioles, yet little is known about thestructure, biophysical properties or assembly kinetics of such fibres. Here I combine live cell imaging of endogenouslytagged rootletin with cell fusion, and find previously unrecognised plasticity in centrosome cohesion. Rootletin formslarge, diffusionally stable, bifurcating fibres, which amass slowly on mature centrioles over many hours from anaphase.Nascent centrioles (procentrioles) in contrast do not form roots, and must be licensed to do so through polo-like kinase 1(PLK1) activity. Transient separation of roots accompanies centriolar repositioning during the interphase, suggesting thatcentrioles organize as independent units, each containing discrete roots. Indeed, forced induction of duplicate centriolepairs allows independent re-shuffling of individual centrioles between the pairs. Thus collectively, these findings suggestthat progressively nucleated polymers mediate the dynamic association of centrioles as either one or two interphasecentrosomes, with implications for the understanding of how non-membrane bound organelles self-organise.

Journal article

Isokane M, Walter T, Mahen R, Nijmeijer B, Hériché J-K, Miura K, Maffini S, Ivanov MP, Kitajima TS, Peters J-M, Ellenberg Jet al., 2016, ARHGEF17 is an essential spindle assembly checkpoint factor that targets Mps1 to kinetochores, The Journal of Cell Biology, Vol: 212, Pages: 647-659, ISSN: 0021-9525

To prevent genome instability, mitotic exit is delayed until all chromosomes are properly attached to the mitotic spindle by the spindle assembly checkpoint (SAC). In this study, we characterized the function of ARHGEF17, identified in a genome-wide RNA interference screen for human mitosis genes. Through a series of quantitative imaging, biochemical, and biophysical experiments, we showed that ARHGEF17 is essential for SAC activity, because it is the major targeting factor that controls localization of the checkpoint kinase Mps1 to the kinetochore. This mitotic function is mediated by direct interaction of the central domain of ARHGEF17 with Mps1, which is autoregulated by the activity of Mps1 kinase, for which ARHGEF17 is a substrate. This mitosis-specific role is independent of ARHGEF17’s RhoGEF activity in interphase. Our study thus assigns a new mitotic function to ARHGEF17 and reveals the molecular mechanism for a key step in SAC establishment.

Journal article

Wachsmuth M, Conrad C, Bulkescher J, Koch B, Mahen R, Isokane M, Pepperkok R, Ellenberg Jet al., 2015, High-throughput fluorescence correlation spectroscopy enables analysis of proteome dynamics in living cells, NATURE BIOTECHNOLOGY, Vol: 33, Pages: 384-U91, ISSN: 1087-0156

Journal article

Mahen R, Koch B, Wachsmuth M, Politi AZ, Perez-Gonzalez A, Mergenthaler J, Cai Y, Ellenberg Jet al., 2014, Comparative assessment of fluorescent transgene methods for quantitative imaging in human cells, MOLECULAR BIOLOGY OF THE CELL, Vol: 25, Pages: 3610-3618, ISSN: 1059-1524

Journal article

Keller D, Orpinell M, Olivier N, Wachsmuth M, Mahen R, Wyss R, Hachet V, Ellenberg J, Manley S, Goenczy Pet al., 2014, Mechanisms of HsSAS-6 assembly promoting centriole formation in human cells, JOURNAL OF CELL BIOLOGY, Vol: 204, Pages: 697-712, ISSN: 0021-9525

Journal article

Mahen R, Hattori H, Lee M, Sharma P, Jeyasekharan AD, Venkitaraman ARet al., 2013, A-Type Lamins Maintain the Positional Stability of DNA Damage Repair Foci in Mammalian Nuclei, PLOS ONE, Vol: 8, ISSN: 1932-6203

Journal article

Bolderson E, Savage KI, Mahen R, Pisupati V, Graham ME, Richard DJ, Robinson PJ, Venkitaraman AR, Khanna KKet al., 2012, Kruppel-associated Box (KRAB)-associated co-repressor (KAP-1) Ser-473 phosphorylation regulates heterochromatin protein 1β (HP1-β) mobilization and DNA repair in heterochromatin., J Biol Chem, Vol: 287, Pages: 28122-28131

The DNA damage response encompasses a complex series of signaling pathways that function to regulate and facilitate the repair of damaged DNA. Recent studies have shown that the repair of transcriptionally inactive chromatin, named heterochromatin, is dependent upon the phosphorylation of the co-repressor, Krüppel-associated box (KRAB) domain-associated protein (KAP-1), by the ataxia telangiectasia-mutated (ATM) kinase. Co-repressors, such as KAP-1, function to regulate the rigid structure of heterochromatin by recruiting histone-modifying enzymes, such HDAC1/2, SETDB1, and nucleosome-remodeling complexes such as CHD3. Here, we have characterized a phosphorylation site in the HP1-binding domain of KAP-1, Ser-473, which is phosphorylated by the cell cycle checkpoint kinase Chk2. Expression of a nonphosphorylatable S473A mutant conferred cellular sensitivity to DNA-damaging agents and led to defective repair of DNA double-strand breaks in heterochromatin. In addition, cells expressing S473A also displayed defective mobilization of the HP1-β chromodomain protein. The DNA repair defect observed in cells expressing S473A was alleviated by depletion of HP1-β, suggesting that phosphorylation of KAP-1 on Ser-473 promotes the mobilization of HP1-β from heterochromatin and subsequent DNA repair. These results suggest a novel mechanism of KAP-1-mediated chromatin restructuring via Chk2-regulated HP1-β exchange from heterochromatin, promoting DNA repair.

Journal article

Mahen R, Venkitaraman AR, 2012, Pattern formation in centrosome assembly, CURRENT OPINION IN CELL BIOLOGY, Vol: 24, Pages: 14-23, ISSN: 0955-0674

Journal article

James JR, McColl J, Oliveira MI, Dunne PD, Huang E, Jansson A, Nilsson P, Sleep DL, Goncalves CM, Morgan SH, Felce JH, Mahen R, Fernandes RA, Carmo AM, Klenerman D, Davis SJet al., 2011, The T Cell Receptor Triggering Apparatus Is Composed of Monovalent or Monomeric Proteins, JOURNAL OF BIOLOGICAL CHEMISTRY, Vol: 286, Pages: 31993-32001

Journal article

Mahen R, Jeyasekharan AD, Barry NP, Venkitaraman ARet al., 2011, Continuous polo-like kinase 1 activity regulates diffusion to maintain centrosome self-organization during mitosis, PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, Vol: 108, Pages: 9310-9315, ISSN: 0027-8424

Journal article

Amorim MJ, Bruce EA, Read EKC, Foeglein A, Mahen R, Stuart AD, Digard Pet al., 2011, A Rab11-and Microtubule-Dependent Mechanism for Cytoplasmic Transport of Influenza A Virus Viral RNA, JOURNAL OF VIROLOGY, Vol: 85, Pages: 4143-4156, ISSN: 0022-538X

Journal article

Jeyasekharana AD, Ayoub N, Mahen R, Ries J, Esposito A, Rajendra E, Hattori H, Kulkarni RP, Venkitaraman ARet al., 2010, DNA damage regulates the mobility of Brca2 within the nucleoplasm of living cells, PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, Vol: 107, Pages: 21937-21942, ISSN: 0027-8424

Journal article

Ayoub N, Rajendra E, Su X, Jeyasekharan AD, Mahen R, Venkitaraman ARet al., 2009, The carboxyl terminus of Brca2 links the disassembly of Rad51 complexes to mitotic entry., Curr Biol, Vol: 19, Pages: 1075-1085

BACKGROUND: The Rad51 recombinase assembles on DNA to execute homologous DNA recombination (HR). This process is essential to repair replication-associated genomic lesions before cells enter mitosis, but how it is started and stopped during the cell cycle remains poorly understood. Rad51 assembly is regulated by the breast cancer suppressor Brca2, via its evolutionarily conserved BRC repeats, and a distinct carboxy (C)-terminal motif whose biological function is uncertain. Using "hit-and-run" gene targeting to insert single-codon substitutions into the avian Brca2 locus, we report here a previously unrecognized role for the C-terminal motif. RESULTS: We show that the avian C-terminal motif is functionally cognate with its human counterpart and identify point mutations that either abolish or enhance Rad51 binding. When these mutations are introduced into Brca2, we find that they affect neither the assembly of Rad51 into nuclear foci on damaged DNA nor DNA repair by HR. Instead, foci disassemble more rapidly in a point mutant that fails to bind Rad51, associated with faster mitotic entry. Conversely, the slower disassembly of foci in a point mutant that constitutively binds Rad51 correlates with delayed mitosis. Indeed, Rad51 foci do not persist in mitotic cells even after G2 checkpoint suppression, suggesting that their disassembly is a prerequisite for chromosome segregation. CONCLUSIONS: We conclude that Rad51 binding by the C-terminal Brca2 motif is dispensable for the execution of HR but instead links the disassembly of Rad51 complexes to mitotic entry. This mechanism may ensure that HR terminates before chromosome segregation. Our findings assign a biological function for the C-terminal Brca2 motif in a mechanism that coordinates DNA repair with the cell cycle.

Journal article

Palmer CP, Mahen R, Schnell E, Djamgoz MBA, Aydar Eet al., 2007, Sigma-1 receptors bind cholesterol and remodel lipid rafts in breast cancer cell lines, CANCER RESEARCH, Vol: 67, Pages: 11166-11175, ISSN: 0008-5472

Journal article

Mahen R, A DNA-based voltmeter for organelles

Journal article

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