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How does the chromatin- and RNA-associated protein SAF-A support chromosomal DNA replication and promote cancer?


School of Medicine, Medical Sciences & Nutrition

Aberdeen United Kingdom Biochemistry Cancer Biology Genetics Molecular Biology

About the Project

This project will elucidate how Scaffold Attachment Factor-A (SAF-A) promotes robust and rapid DNA replication, and investigate the contribution of SAF-A on tumour development.

 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 that controls 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 body 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 for initiation, and rapid replication fork progression [8]. Moreover, cells depleted for SAF-A suffered from replication stress and tend to enter quiescence inappropriately [8]. These findings suggest that SAF-A abundance affects cellular competence for DNA replication and proliferation. Considering that cancer cells are under constant replication stress [9, 10], we hypothesise SAF-A overexpression helps tumour development through the management of replication stress.

 RESEARCH PROJECT

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

 1. Does the abundance of SAF-A impact DNA replication?

The PhD project will examine whether the abundance of SAF-A impacts DNA replication, by testing how overexpressing and depleting SAF-A affects resistance to DNA replication inhibitors. 

 2. Are RNA- and DNA-binding of SAF-A required for its function in DNA replication?

The student will investigate whether the RNA- or DNA-binding functions of SAF-A are needed to promote DNA replication, and cellular resistance to replication inhibition.

 3. Which chromatin proteins are affected by SAF-A?

To understand how SAF-A affects the replication machinery, the impact on chromatin composition of abrogating the RNA- and DNA-binding function of SAF-A will be investigated using proteomics.

 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 and contributions to tumour development. Long-term, this research will inform cancer diagnostics.

 The research will be 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 successful student will join an extended group of researchers sharing interests in the biology of chromosomes maintenance. The supervisory team is experienced in the experimental approaches involved, and will provide strong support and training for this research programme.  

APPLICATION PROCEDURE:

Formal applications can be completed online: https://www.abdn.ac.uk/pgap/login.php. You should apply for Degree of Doctor of Philosophy in Medical Sciences, to ensure that your application is passed to the correct person for processing.

NOTE CLEARLY THE NAME OF THE SUPERVISOR AND EXACT PROJECT TITLE ON THE APPLICATION FORM. 

 


Funding Notes

This is a 4 year PhD position funded by the School of Medicine, Medical Sciences and Nutrition. Full funding is available to UK candidates only. Overseas candidates can apply for this studentship but will have to find additional funding to cover the difference between overseas and home fees (approximately £17,000 per annum).
Candidates should have (or expect to achieve) a minimum of a 2.1 Honours degree in a relevant subject. Applicants with a minimum of a 2.2 Honours degree may be considered provided they have a Merit/Commendation/Distinction as Master's level.

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).
7. Yates, T.M., et al., Am J Med Genet A, 173: 3003-3012 (2017).
8. Connolly, C., et al. (2021) SAF-A promotes origin licensing and replication fork progression to ensure robust DNA replication. bioRxiv, DOI: 10.1101/2021.03.22.436394.
9. Gaillard, H., et al., Nat Rev Cancer, 15: 276-289 (2015).
10. Macheret, M. and T.D. Halazonetis, Annu Rev Pathol, 10: 425-448 (2015).

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