Prof Noel Lowndes
Established Professor of Biochemistry
Director of the CCB
SFI Future Frontiers & EMBO Member
noel.lowndes@universityofgalway.ie

Research interests

  • Role of phosphatidylinositol 3-kinase like kinases (PIKKs) in genome stability
  • Kinesins & 53BP1-dependent DNA double strand break repair
  • Zinc finger protein roles in DNA double strand break signalling & repair
  • Regulation of cytokinetic abscission by ATR

Research overview

Pathways required to maintain genome stability are potently tumour suppressive, while genome instability is a hallmark of cancer. Our research aims to elucidate novel mechanisms controlling genome stability. While our focus is on fundamental cell biology, future translational studies may ultimately have clinical impact. We utilise genome editing, proteomics, in vitro biochemistry and microscopy to identify and dissect novel genome stability factors. Our principle models are established transformed and immortalised human cell lines (e.g. HCT293, HeLa, U2OS, hTERT-RPE1 cells). In addition, we use primary animal fibroblasts (e.g. mouse, bat).

Keywords

ATM, ATR, abscission, checkpoints, DNA repair, kinesins, 53BP1

Selected Figures

Characterisation of the binding surface on the Tudor domain of 53BP1 that interacts with a novel Tudor-interacting motif (TIM) in the nuclear kinesin, KIF18B. Residue W1495 (purple), which separates the known pocket for binding Histone H4K20me2 from the shallower pocket that binds KIF18B-TIM, is required to bind both . The silver stained gel on the left is an SDS-PAGE analysis of an in vitro binding assay using purified recombinant Flag-tagged 53BP1 Tudor domain (WT and mutants, as indicated) with biotinylated H4K20me2 or KIF18B-TIM peptides. Residues D1521 and Y1502 (in orange) and C1525 and S1497/S1496 (in blue) are specific to H4K20me2 and TIM, respectively. [Source]
Cytokinetic abscission occurs when the membrane remodelling ESCRT-III complex re-localises from the cytokinetic midbody to abscission sites on one side (“1o cut”) and then the other (“2o cut”) side of the midbody. The critical ESCRT-III component for abscission is CHMP4B. While ATR localises to the midbody, specifically during late cytokinesis, it does not localise to the sites of abscission. ATR has a regulatory role, rather than in abscission per se. [Source]
A four year old non-Seckel patient presenting at the Cleveland Clinic (Ohio, USA) with developmental delays, autism and acute leukemia was determined to be a compound ATR heterozygote inheriting a known Seckel mutation from his father (intron 2 c.151+4A>G) and a novel missense mutation in the ATR allele inherited from his mother (c.140 A>T; D47V). Molecular Dynamic simulations (with Leif Eriksson, University of Gothenberg, Sweden) indicate the loss of a salt bridge between ATR (in green) and ATRIP (in blue). The ATR-D47V mutation disrupts helix-coil transitions resulting in a less dynamic ATR N-terminal structure that interacts less efficiently with ATRIP resulting in reduced ATR activity

Key Research techniques

  • Genome editing
  • Protein biochemistry & proteomics
  • DNA damage & cell cycle assays
  • Fluorescence & expansion microscopy

Lab Members

  • Dr Ilze Skujina (Post-Doc)
  • Dr Floriane Pereira (Post-Doc)
  • Emer Brennan (PhD)
  • Eoin Gillespie (PhD)
  • Sabrinna Crowley (PhD)
  • Peng Wu (PhD)
  • Anna-Marie Meaney (RA & MSc)

Mentoring/Hosting

Dr Janna Luessing
Senior Researcher
SFI-IRC Pathway Programme
janna.luessing@universityofgalway.ie

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Selected publications

Most Recent Publications

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Get in Touch!

noel.lowndes@universityofgalway.ie