Student Bursary funds important research 

The Allan Reid Student Research Bursary was awarded to Nicole Ball from the University of East Anglia. [2019-2020]

The Paget’s Association awarded the Allan Reid Student Bursary Award to Nicole Ball from the University of East Anglia. Nicole is a second year PhD student performing research under supervision of Dr Darrell Green, who is a Lecturer in Medicine at Norwich Medical School, and Professor William Fraser, who is the school’s head and a Consultant Metabolic Physician at the Norfolk and Norwich University Hospital. Nicole received the award at the Paget’s Information Day, which was held in Nottingham. Here, they discuss Nicole’s new research project.

Application of iCLIP technology to determine the role of SQMTM1 as an RNA binding protein

Introduction
Paget’s Disease of Bone is the second most common metabolic bone disorder after osteoporosis and affects 1-5% of people with British lineage over the age of 55. In very rare cases (less than one in a thousand cases), there can be transformation into Paget’s associated osteosarcoma, which is a type of bone cancer. This rare complication is thought to initiate due to genetic changes induced by the abnormal turnover of a type of bone cell called an osteoblast, which is responsible for producing new bone. Abnormal turnover of osteoblasts is one of several steps that make up Paget’s disease.

Genes within our DNA provide the instructions for producing proteins. Proteins are complex molecules that are required for the structure and function of cells, hormones, signalling molecules (responsible for transmitting information between cells) and tissues within the body. It is vital that genes for producing proteins are not faulty because incorrect instructions can lead to incorrect construction of proteins. Faulty proteins can cause serious problems within the body. For example, proteins involved in bone turnover (the process of breaking down and producing new bone) could, if faulty, lead to Paget’s disease. There are around 23,000 genes contained within each human cell. Nine genes have been identified as having a likely role in Paget’s if they are abnormal. There are several other genes also being investigated for their role in the condition.

Current Research
Sequestosome 1 (SQSTM1) is a gene that we know has an important role in Paget’s disease. In so called “familial” Paget’s where more than one person in an immediate family has the disease, almost half of cases harbour a faulty SQSTM1 gene. The SQSTM1 gene provides the instructions for the SQSTM1 protein, which has several cellular roles including progression of bone turnover and protecting DNA from damage. In Paget’s disease the abnormal gene, SQSTM1, produces abnormal SQSTM1 protein. Most known faults to SQSTM1 lead to a whole section of the SQSTM1 protein being deleted. This particular section of the SQSTM1 protein is usually required for the cell to switch off SQSTM1 when it is not needed. Abnormal SQSTM1 with the missing section cannot be switched off and so accelerates Paget’s disease.

DNA contains the gene SQSTM1. The DNA on the left contains the normal form of SQSTM1 gene that when expressed as RNA (a genetic “middleman”) carries the instructions from DNA before producing a functional SQSTM1 protein.

The DNA on the right contains faulty SQSTM1. Incorrect RNA instructions cause the production of abnormal SQSTM1 protein. Most of the identified faults cause the “tail” end of SQSTM1 to be missing, which is an important part of the protein used to deactivate SQSTM1 later on. As the tail end is missing, SQSTM1 cannot be switched off and is perpetually active.

Interestingly, we recently found that abnormal SQSTM1 may have a protective effect against the development of cancer, specifically, Paget’s associated osteosarcoma. Our research has shown that another molecule called microRNA-16 switches off faulty RNA containing faulty SQSTM1. Whilst this appears to be a protective function against the production of abnormal SQSTM1 protein, it can have the negative effect of switching off SQSTM1 entirely leading to a lack of DNA protection and therefore Paget’s associated osteosarcoma.

Future research funded by the bursary
We speculate that there is a “battle” between SQSTM1 and microRNA-16. Recent experiments have shown that while microRNA-16 is able to switch off production of SQSTM1 RNA, SQSTM1 protein may be able to switch off microRNA-16. The bursary will fund new experiments to develop a new method to characterise the physical interaction between SQSTM1 and microRNA-16 at the molecular level. We hypothesise that if we understand the complexities of this “battle” we can further understand the workings of SQSTM1 and its role in Paget’s disease and Paget’s associated osteosarcoma. In the future, we may be able to interfere with this battle and possibly other battles with SQSTM1 as a new line of treatment.