Career History

BA (Genetics) Trinity College Dublin

PhD University of Edinburgh (with Adrian Bird)

Post-Doc Fred Hutchinson Cancer Centre, Seattle (with Ron Reeder)

Lecturer/Senior Lecturer University of Dundee (Medical school)Research funded by Wellcome Trust project and MRC program grants Professor in Biochemistry NUI Galway (since Sept 2008)Research funded by SFI

Prof Brian McStayWellcome Trust Senior Investigator Award

April 2015- March 2020

Area of researchimportance of the candidate’s research questions

Chromosomal contextGenomic stability

Nucleolar fusion

Altered form and function of nucleoli in human disease

(Cancer and ribosomopathies)

Active v Silent Unsequenced

Our contributionsthe candidate’s track record and approach

Extensive binding of UBF across rDNA arrays defines active NORs

Active v Silent

Sullivan, G.J., Bridger, J.M., Cuthbert, A.P., Newbold, R.F., Bickmore, W.A. and McStay, B. (2001) EMBO J, 20, 2867-2874.

O'Sullivan, A.C., Sullivan, G.J. and McStay, B. (2002) Mol Cell Biol,22, 657-668.

Mais, C., Wright, J.E., Prieto, J.L., Raggett, S.L. and McStay, B (2005)Genes and Development, 19, 50-64.

Prieto, J.L. and McStay, B. (2007) Genes and Development, , 21, 2041-2054.

Integrate Mb arrays of artificial UBF binding sites

Novel 20 constrictions

appear?

Array is 1.4Mb

Pseudo-NORs

Our contributions

Grob, A., Colleran, C. and McStay, B. (2014) Genes and Development, 28, 220-230.

The neo-NOR cassette (20.4kb)

Human promoter

XEn elements

Mouse coding sequences

18S 5.8S 28S

Transcriptional terminator

5’ETS

ITS1 ITS2 3’ETS

By constructing synthetic nucleoli in human cells, neo-nucleoli, we were able to prove that nucleolar formation is a staged process where UBF-dependent mitotic bookmarking precedes

function-dependent nucleolar assembly.

Our contributions

~95% identical and high level segmental duplication

The first description of the genomic architecture of NORs

and surrounding sequences on acrocentric p-arms

>99% identical and unique to acrocentric p-arms

PJ DJ

Our contributions

Floutsakou, I., Agrawal, S., Nguyen, T.T., Seoighe, C., Ganley, A.R. and McStay, B. (2013) Genome Research, 23, 2003-2012.

A localized nucleolar damage response facilitates recruitment of the

homology directed repair machinery independent of cell cycle stage

Our contributions

van Sluis, M and McStay, B. (2015) Under revision for Genes and Development

• Contribute to completion of human genome and a description of its 4D organisation in human cells

Outcomes

• Finally describe the chromosomal context of NORs and how this influences the biology of nucleoli

• Provide new tools for nucleolar research and exploring its role in human disease

1. Genomic architecture of acrocentric p-arms

2. Regulation of NOR function and nucleolar morphology

3. Chromosomal context and genomic stability of NORs

Approaches

Genomics, Cell biology, Genome editing, Bioinformatics

Specific aims

The Genomic Architecture of Human NORs and its Role in Nucleolar Biology

Application Process

Motivations for application• the knowledge that our current work is our most important• advice from the CCB Scientific advisory board • the current funding climate in Ireland

1st Oct/2014Advised that the Wellcome Trust’s Molecular Basis of Cell Function Expert Review Group has considered my application and has recommended that it progress to interview by the Interview Panel

18th July/2014Submitted application for Senior Investigator Award , ‘The genomic architecture of human nucleolar organizer regions and its role in nucleolar biology . ’

27th Nov/2014Received comments from 4 referees

4th Dec/2014Interview

Questions asked of reviewers

• What is your view of the quality and importance of the candidate’s research questions?

• What is your view of the candidate’s approach?

• What is your view of the candidate’s track record, relative to his or her career stage?

• What is your view of the research environment?

• Overall Assessment

• Data Management and Sharing

Interview structure

The interview consists of a ten minute presentation of the research proposal followed by approximately twenty minutes of questions from the Panel.

The presentation is strictly limited to three slides, without any animation or movies. Cannot understate importance of the quality and preparedness of presentation.

The Interview Panel consists of a Co-Chair and core members. Additional individuals from the Expert Review Groups and other specialists may be invited, as appropriate, to join the Interview Panel for each round. In addition to Panel members, Wellcome Trust staff and Governors will be in attendance

Panel included 8 scientists (including at least 1 specialist), 4 from the US, 3 from the UK and 1 from GermanyQuestions arose from the presentation and from referees comments. No sense of outcome from the interview

Interview (Dec 4th)

Decision (Dec 12th)

Phone call informing me that I was successful, and that I would receive the full amount requested.Required to submit part B of application including the detailed budget.

Award Letter (Jan 23rd)

Funding details

Final Comment

The entire process focused on the science.