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EASTBIO How does the RNA-associated chromatin component SAF-A ensure chromosomal DNA replication?


School of Medicine, Medical Sciences & Nutrition

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Dr S Hiraga , Dr T Ly No more applications being accepted Competition Funded PhD Project (Students Worldwide)

About the Project

Supervisors:

Dr Shin-ichiro Hiraga (University of Aberdeen)
https://www.abdn.ac.uk/smmsn/people/profiles/s.hiraga

Dr Tony Ly (University of Dundee)
http://dynamic-proteomes.squarespace.com

This project will elucidate how Scaffold Attachment Factor-A (SAF-A) promotes robust and rapid DNA replication.

BACKGROUND
Chromatin structure is closely intertwined with chromatin activities, such as DNA replication and transcription [1]. Scaffold Attachment Factor-A (SAF-A), also known as heteronuclear RNP U (HNRNPU), is an RNA- and DNA-binding protein implicated in defining chromatin structure in the nucleus [2]. The expression level of SAF-A is linked to cell proliferation: SAF-A expression is elevated in a wide range of cancers, particularly breast cancers [3, 4]. Conversely, reduced SAF-A level is associated with development disorders such as microcephaly [5-7]. However, direct mechanisms that link SAF-A to proliferation are unknown.
We have discovered that SAF-A is required for robust and rapid DNA replication and cell proliferation. Specifically, we find SAF-A promotes licensing of replication origins, and subsequently rapid replication fork progression [8]. This PhD project will examine the molecular mechanism through which SAF-A affects DNA replication, to elucidate a previously unknown pathway of DNA replication control.

RESEARCH PROJECT
This 4-year PhD project will address 3 main questions:

1. Does the abundance of SAF-A impact DNA replication?
The student will first examine whether the abundance of SAF-A impacts DNA replication, by testing the impact of overexpressing and depleting SAF-A on replication dynamics, and on cellular resistance to DNA replication inhibitors.

2. Does SAF-A control DNA replication through its RNA- or DNA-binding functions?
The student will investigate whether the RNA- or DNA-binding functions of SAF-A are needed to promote DNA replication, and to mediate cellular resistance to replication inhibition.

3. Which chromatin proteins are affected by SAF-A?
To investigate how SAF-A impacts the replication machinery, we will use advanced proteomics to examine how chromatin composition is affected by preventing the RNA- and DNA-binding functions of SAF-A. The defects identified will be followed up in phenotypic analyses to understand the importance of SAF-A for chromatin assembly and its connection with DNA replication.

This research will reveal the mechanism through which SAF-A supports robust DNA replication and cell proliferation; and also the impact of SAF-A on chemoresistance. Long-term, this research will inform cancer diagnostics.

The research will be mainly carried out in the Institute of Medical Sciences located at the Foresterhill campus of the University of Aberdeen. The institute is well-supported by various facilities such as Microscopy, Flow cytometry, Genomics and Proteomics. The expertise of the primary supervisor of Dr Hiraga in molecular and cellular biology will be complemented by the second supervisor Dr Ly’s expertise in chemistry/biochemistry and in proteomics. The student will benefit from belonging to an extended group of laboratories sharing an interest in chromosome maintenance.

Application Procedure:

http://www.eastscotbiodtp.ac.uk/how-apply-0

Please send your completed EASTBIO application form, along with academic transcripts to Alison McLeod at [Email Address Removed]. Two references should be provided by the deadline using the EASTBIO reference form. Please advise your referees to return the reference form to [Email Address Removed].

Funding Notes

This 4 year PhD project is part of a competition funded by EASTBIO BBSRC Doctoral Training Partnership http://www.eastscotbiodtp.ac.uk/how-apply-0. This opportunity is open to UK and International students and provides funding to cover stipend and UK level tuition (limited funding is available to provide international tuition fees). Please refer to UKRI website and Annex B of the UKRI Training Grant Terms and Conditions for full eligibility criteria.

Candidates should have (or expect to achieve) a minimum of a 2:1 UK Honours degree, or the equivalent qualifications gained outside the UK, in a relevant subject.

References

1. Shoaib, M., et al., Nat Commun, 9: 3704 (2018).
2. Nozawa, R.S., et al., Cell, 169: 1214-1227 e1218 (2017).
3. TCGA Research Network. Available from: https://www.cancer.gov/tcga.
4. cBioPortal for Cancer Genomics. Available from: https://www.cbioportal.org/.
5. Durkin, A., et al., Am J Med Genet A, (2020).
6. Leduc, M.S., et al., Am J Med Genet A, 173: 2680-2689 (2017).
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