Brian McStay

Prof Brian McStay
Professor in Biochemistry
Wellcome Investigator
EMBO Member
brian.mcstay@universityofgalway.ie

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Research overview

Nucleoli, sites of ribosome biogenesis and the largest structures in the human nucleus, form around nucleolar organiser regions (NORs) located on the short or p-arms of five different chromosomes referred to as acrocentric chromosomes (see McStay, 2023). NORs comprise ribosomal genes (rDNA) arrays coding for the major RNA components of ribosomes.

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How multiple acrocentric p-arms gather together to form a nucleolus and how NORs partition within nucleoli are important but unanswered questions. Progress has been hampered by the inability to distinguish acrocentric p-arms from each other due to their shared DNA-sequences (see Van Sluis et al, 2019 and Van Sluis et al, 2020).

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To circumvent this, we have developed powerful chromosome-engineering approaches on single human chromosomes held in mono-chromosomal somatic cell hybrids.

Using this transformative technology and Wellcome Investigator funding, we are currently addressing the following aims:

1. Characterise chromosomal requirements for the formation of large multivalent nucleoli
2. Identify factor(s) constraining NOR-territories (see Mangan & McStay, 2021)
3. Explore cellular responses to rDNA DSBs using genome-edited human NORs (see Van Sluis & McStay, 2015)

Keywords

Human acrocentric chromosomes, nucleolar organiser regions (NORs), nucleolus, ribosomal genes (rDNA), rDNA genome stability.

Selected publications

• The p-Arms of Human Acrocentric Chromosomes Play by a Different Set of Rules
• Human nucleoli comprise multiple constrained territories, tethered to individual chromosomes
• NORs on human acrocentric chromosome p-arms are active by default and can associate with nucleoli independently of rDNA 
• Human NORs, comprising rDNA arrays and functionally conserved distal elements, are located within dynamic chromosomal regions
• A localized nucleolar DNA damage response facilitates recruitment of the homology-directed repair machinery independent of cell cycle stage

Most Recent Publications

• Visualization and quantification of rDNA instabilities in mammalian cells and mouse models
• Nucleolar FRG2 lncRNAs inhibit rRNA transcription and cytoplasmic translation, linking FSHD to dysregulation of muscle-specific protein synthesis
• LINE1 elements at distal junctions of rDNA repeats regulate nucleolar organization in human embryonic stem cells

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