Brian McStay

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

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Research interests

• Human acrocentric chromosomes
• Chromosomal context of human NORs
• Nucleolar formation and organisation
• Genome stability of rDNA arrays

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

• Topological stress triggers persistent DNA lesions in ribosomal DNA with ensuing formation of PML-nucleolar compartment
• Monoallelically expressed noncoding RNAs form nucleolar territories on NOR-containing chromosomes and regulate rRNA expression
• Human pangenome supports analysis of complex genomic regions

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