Our former PhD student Søren Hough is lead author on a paper published in EMBO Molecular Medicine by Steve Jackson’s Group with colleagues in Birmingham, Mainz, Kansas City, Belfast, Angers, East Jerusalem, London, Bristol, Geneva and Heidelberg.
DNA repair and replication are crucial processes in our cells. These pathways help our genome resist the tens of thousands of breaks our DNA undergoes per cell per day as a result of exposure to the sun, chemicals, and other sources of stress. In the paper, the Jackson Lab was interested in finding proteins that had not previously been connected to DNA repair and replication. They performed a screen using the genome editing tool CRISPR to sift through a pool of candidates. This led them to MAEA, a protein that at the time was primarily associated red blood cell development and glucose production.
They showed that MAEA is important for repairing specific kinds of replication-associated DNA damage. They also saw, with help from collaborators at the University of Birmingham, that without MAEA cells struggle to replicate their DNA efficiently. These observations may one day be important for cancer patient stratification or drug design. In parallel, the Jackson Lab worked with an international team of clinicians to identify a cohort of eight patients 16 years of age and younger who have variants in their copy of the MAEA gene. All the patients exhibited some degree of global developmental delay that can be traced back to these genetic differences.
The paper characterised the neurodevelopmental disorder observed in the cohort DIADEM (Developmental delay and Intellectual disability Associated with DEfects in MAEA). When DIADEM patient variants were modelled in the lab, it was found that they lead to severe impairment of DNA repair and replication, just like MAEA loss. It is hoped the work will help inform DIADEM families and help clinicians better understand their condition as they provide lifelong care for their patients.
Read the paper: Loss of CTLH component MAEA impairs DNA repair and replication and leads to developmental delay
Read more about Søren Hough's research for the paper and the description of a new diagnosis, DIADEM, on the Churchill College website.