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The role of hnRNPUL proteins in the DNA damage response.


Project Description

Applications Open to: Someone who is very highly committed to scientific research with a 2.1 or equivalent degree in a science subject and can provide their own funding.

Applications including a CV and covering letter should be sent to Yvonne Palmer, School of Cancer Sciences, College of Medical and Dental Sciences, University of Birmingham, Edgbaston, Birmingham B15 2TT or email . Please quote the title of this studentship as the subject of your email.

The cellular genome is subject to continuous insult resulting in tens of thousands of lesions in the DNA per cell per day. The damage can take the form of DNA double strand breaks DSBs), single strand breaks, inter-strand cross links and base modifications. To counteract this, a complex series of pathways, collectively known as the DNA damage response (DDR), has evolved and this is able to detect and, if possible, repair the DNA. The inability to maintain this genomic integrity is a major underlying cause of cancers as well as other diseases. The repair pathways are based on the activities of three related kinases-Ataxia Telangiectasia mutated (ATM), ATM and Rad3-related (ATR) and DNA dependent protein kinase (DNA-PK). Following detection of DNA damage, one or more of the kinases are activated leading to phosphorylation of multiple downstream targets, recruitment of specific repair proteins to the site of damage and repair of the lesion if the damage is not too great. The DDR pathways comprise a large number of components, with, simplistically, specific proteins involved in homologous recombination, non-homologous end joining and single strand break repair amongst others. We have shown that heterogeneous nuclear ribonucleoprotein U-like (hnRNPUL) proteins 1 and 2 play key, previously unknown, roles in cellular responses to DSBs. We have identified human hnRNPUL1 and -2 as binding partners for the DSB sensor complex MRE11-RAD50-NBS1 (MRN) and demonstrated that hnRNPUL1 and -2 are recruited to sites of DNA damage in an interdependent manner that requires MRN. Moreover, we have also shown that hnRNPUL1 and -2 stimulate DNA-end resection and promote ATR-dependent signalling and DSB repair by homologous recombination, thereby contributing to cell survival upon exposure to DSB-inducing agents. More recently, we have shown that hnRNPUL-1 can bind ATP and has associated protein kinase activity. It is the purpose of this project to investigate these two observations in more detail. Specifically, we will determine whether the kinase activity is inherent to hnRNPUL-1 or due to an associated protein kinase. If this latter is the case the kinase will be identified by mass spectrometry and the binding sites on the two proteins mapped; thus, the interaction will be characterised in detail. If, as seems more likely, hnRNPUL-1 has inherent kinase activity we will investigate, using site-directed mutagenesis, to what extent this, and its ability to bind nucleotides, is required for its role in the DDR. For example, is it necessary for recruitment to sites of DNA damage and for interaction with the MRN complex and other DDR proteins to which it has been shown to bind. Similarly, how important is hnRNPUL-1’s ability to bind RNA and to what extent does this impact on its DDR properties? It is expected that these sorts of approaches will help us to understand the mode of action of a DDR protein which has a quite unique activity

Funding Notes

Self-funded

References

1.The DNA damage response: ten years after. Harper J.W. and Elledge S.J. Mol. Cell, 2007 28, 739-45.
2.The causes and consequences of genetic heterogeneity in cancer evolution. Burrell RA, McGranahan N, Bartek J, Swanton C.Nature. 2013; 501:338-45.
3.More than just a focus: The chromatin response to DNA damage and its role in genome integrity maintenance.Lukas J, Lukas C, Bartek J.Nat Cell Biol. 2011; 13:1161-9.
4.The DNA-damage response in human biology and disease.
Jackson SP, Bartek J.Nature. 2009; 461:1071-8.
5 Regulation of DNA-end resection by hnRNPU-like proteins promotes DNA double-strand break signaling and repair.Polo SE, Blackford AN, Chapman JR, Baskcomb L, Gravel S, Rusch A, Thomas A, Blundred R, Smith P, Kzhyshkowska J, Dobner T, Taylor AM, Turnell AS, Stewart GS, Grand RJ, Jackson SP. Mol Cell. 2012;45(4):505-512

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