Research

Our research interests

I have previously studied how specialised chromatin domains, namely telomeres, are spatially organised within the nucleus by sumoylation. Current projects involve studying the role of chromatin remodelling enzymes in genome stability and their interplay with telomeres.

Previous research projects

SUMO regulates telomere localisation in S. cerevisiae

SUMO (Small Ubiquitin-like modifier) is a post-translational modification added onto lysine residues and has been linked to genome stability processes. We observed that deletion of the PIAS-like SUMO E3 ligase SIZ2, but not other E3 ligases, led to telomere delocalisation from the nuclear periphery. We showed that Siz2 promotes both telomere anchoring pathways of budding yeast (Sir4 and Yku70/80) and sumoylates these proteins in vivo. Importantly, we showed that the defect in Yku70 and Yku80-4 mediated chromatin anchoring in siz2Δ cells can be overcome by making a linear fusion of Yku70 or Yku80 to SUMO. Deletion of SIZ2 also resulted in a telomerase-dependent increase in telomere length. Remarkably, the localisation and length phenotypes seen in siz2Δ cells appear to be functionally linked. We found that critically short telomeres detach from the nuclear periphery when they are most efficiently elongated. Our study was the first to show an effect of sumoylation on telomere anchoring and argues that Siz2-mediated control of telomere position helps regulate stable telomere maintenance.Figure 1. Model of Siz2 mediated effects on telomere localisation and elongation (Ferreira et al NCB 2011)

Characterising C. elegans telomere localisation

We have extended our work in yeast by looking at telomere localisation within the multicellular animal, C. elegans. Using a telomere FISH protocol that we optimised (Figure 2), we find that C. elegans telomeres are preferentially bound to the nuclear periphery. This perinuclear association increases during embryogenesis and persists in later larval stages. Remarkably, we find that, as in yeast, PIAS-mediated sumoylation is required for telomere anchoring in C. elegans, being dependent on the SUMO E3 ligase GEI-17. We show that telomere position is independent of the Ku complex and of H3 K9 methylation but instead is dependent on the shelterin component POT-1 anchoring at nuclear envelope to SUN-1. To our knowledge, this is the first characterisation of telomere localisation and anchoring in C. elegans.Figure 2. Telomere (red) and DNA (grey) staining of pachytene cells within the C. elegans germline (Ferreira et al JCB 2013).

Ongoing research projects

Chromatin remodelling and genome stability

ATP-dependent chromatin remodeling enzymes (Snf2-family ATPases) are a large class of motor proteins that have increasingly been shown to be important for DNA repair. Additionally, mutations in a number of Snf2 proteins lead to various developmental disorders as well as carcinogenesis in humans. However, despite their importance, the mechanism by which many Snf2 proteins promote genome stability remains poorly understood. This represents not only a lack of understanding of a fundamental biological process but also a lost opportunity to manipulate genome stability processes for medical benefit.

There is significant interplay between Snf2-family proteins and the sumoylation pathway. Many chromatin remodelling enzymes are SUMO modified, and chromatin remodelling enzymes are required to mediate SUMO-directed transcriptional repression. Understanding the role of sumoylation in Snf2 function may provide an important means to modulate their function.

Uls1: a Snf2-family StUbl

The chromatin remodelling enzymes Uls1 has recently been show to have SUMO targeted ubiquitin ligase (STUbL) activity.  Loss of Uls1 or inactivation of its ATPase activity results in strong sensitivity to the DNA intercalating drug acriflavine and subsequent activation of the DNA damage checkpoint. We are currently looking at Uls1’s mechanism of action and how it contributes to genome stability.

Using C. elegans to understand ATRX

Mutation of ATRX in humans causes alpha-thalassemia, mental retardation (ATRX) syndrome and is also linked to a sub-type of cancers characterised by the alternative lengthening of telomeres (ALT) pathway. We are studying XNP-1, the worm homolog of ATRX, to better understand the connections between the developmental and telomeric roles of ATRX.

Group Members

Dr Helder Ferreira

I graduated with a B.Sc. Honours degree from Imperial College London and spent a year working in GlaxoWellcome before obtaining a PhD from the University of Dundee with Prof. Tom Owen-Hughes. I then did a postdoc in Switzerland at the Friedrich Miescher Institute with Prof. Susan Gasser before joining the School of Biology as a lecturer in 2013.

Our research focusses on chromatin dynamics from local chromatin structure to global nuclear organization and how this regulates cellular processes. In particular, I am interested in ATP-dependent chromatin remodelling enzymes and telomere maintenance. My goal is to understand how the cross-talk between these systems is regulated within a developmental context and to uncover novel targets of chromatin remodelling enzymes. This is done by combining forward genetic analysis in budding yeast and C. elegans with biochemistry to obtain mechanistic insight into novel chromatin remodelling enzymes and the means by which they affect telomere function.

Dr Helder Ferreira
Biomolecular Sciences Building
University of St Andrews
North Haugh
St Andrews
KY16 9ST
Fife
UK

tel: 01334 463425
fax: 01334 462495
room: B303
email: [email protected]

---

Karim Hussain

Dr Katerina Zabrady

Amy Swanston

Publications

Contact

Dr Helder Ferreira
Biomolecular Sciences Building
University of St Andrews
North Haugh
St Andrews
KY16 9ST
Fife
UK

tel: 01334 463425
fax: 01334 462495
room: B303
email: [email protected]