DNA double-strand break repair, immunodeficiency and the RIDDLE syndrome

Abstract

DNA double-strand break (DSB) repair is an essential cellular process required to maintain genomic integrity in the face of potentially lethal genetic damage. Failure to repair a DSB can trigger cell death, whereas misrepair of the break can lead to the generation of chromosomal translocations, which is a known causative event in the development or progression of cancer. DSBs can be induced following exposure to certain exogenous agents, such as ionising radiation or radiomimetic chemicals, as well as occurring naturally as intermediates of normal physiological processes, in particular during B and T cell antigen receptor assembly. Human syndromes with deficiencies in DSB repair commonly exhibit immunodeficiency, highlighting the critical nature of this pathway for development and maturation of the immune system. In this article we review the different pathways utilized by the cell to repair DSBs and how an inherited defect in some of the genes that are critical regulators of this process can be the underlying cause of human disorders associated with genome instability and immune system dysfunction. We focus on a newly described human immunodeficiency disorder called radiosensitivity, immunodeficiency dysmorphic features and learning difficulties (RIDDLE) syndrome, with particular reference to the function of the defective gene, RNF168. We also consider the implications of this finding on the mechanisms controlling development of the immune system.

Keywords::

• 53BP1
• ataxia-telangiectasia
• DNA damage response
• DNA double-strand break repair
• immunodeficiency
• Nijmegen breakage syndrome
• radiosensitive severe combined immunodeficiency
• RIDDLE syndrome
• RNF168

Acknowledgements

The authors would like to thank Malcolm Taylor, Tanja Stankovic, Fay Hollins and Roger Grand for critical reading of the manuscript.

Financial & competing interests disclosure

Rachel M Blundred is funded by an MRC project grant and Grant S Stewart is funded by a CR-UK Career Development Fellowship and a Lister Institute Research Prize. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.