1. ¹Institute of Cancer Biology and Centre for Genotoxic Stress Research, Danish Cancer Society, Copenhagen, Denmark
2. ²Institute of Molecular Genetics, Academy of Sciences of the Czech Republic, Prague, Czech Republic
3. ³Department of Pathology, Copenhagen University Hospital, Copenhagen, Denmark
4. ⁴Department of Pathology, The Norwegian Radium Hospital, University of Oslo, Oslo, Norway
5. ⁵Department of Growth and Reproduction, Copenhagen University Hospital, Copenhagen, Denmark
6. ⁶Institute of Veterinary Biochemistry and Molecular Biology, Universiy of Zürich, Zürich, Switzerland
7. ⁷The Gurdon Institute, Cambridge, UK

Correspondence: Professor J Bartek, Institute of Cancer Biology and Centre for Genotoxic Stress Research, Danish Cancer Society, Strandboulevarden 49, Copenhagen DK-2100, Denmark. E-mail: jb@cancer.dk

⁸These authors contributed equally to this work.

Received 5 February 2007; Revised 14 March 2007; Accepted 26 April 2007; Published online 4 June 2007.

Abstract

MDC1 and 53BP1 are critical components of the DNA damage response (DDR) machinery that protects genome integrity and guards against cancer, yet the tissue expression patterns and involvement of these two DDR adaptors/mediators in human tumours remain largely unknown. Here we optimized immunohistochemical analyses of human 53BP1 and MDC1 proteins in situ and identified their virtually ubiquitous expression, both in proliferating and quiescent, differentiated tissues. Focus formation by 53BP1 and/or MDC1 in human spermatogenesis and subsets of breast and lung carcinomas indicated physiological and 'pathological' activation of the DDR, respectively. Furthermore, aberrant reduction or lack of either protein in significant proportions of carcinomas supported the candidacy of 53BP1 and MDC1 for tumour suppressors. Contrary to carcinomas, almost no activation or loss of MDC1 or 53BP1 were found among testicular germ-cell tumours (TGCTs), a tumour type with unique biology and exceptionally low incidence of p53 mutations. Such concomitant presence (in carcinomas) or absence (in TGCTs) of DDR activation and DDR aberrations supports the roles of MDC1 and 53BP1 within the ATM/ATR-regulated checkpoint network which, when activated, provides an early anti-cancer barrier the pressure of which selects for DDR defects such as p53 mutations or loss of 53BP1/MDC1 during cancer progression.