The integrity of our chromosomal material is dependent upon the efficient repair of DNA lesions that are caused by exogenous agents, such as UV and ionizing radiation. Without comprehensive DNA repair and surveillance systems, broken chromosomes and mutations accumulate in cells leading to apoptosis, which could have devastating consequences in growth and development of an organism. Lost of genome integrity can also lead to cell transformation, a precursor of cancer development. Many cancer suppressor genes are linked to DNA repair. Therefore, understanding the roles of these cancer suppressor proteins will not only allow us to understand mechanisms of different repair pathways but also how they are regulated and coordinated with each other as caretakers of the genome.
A set of proteins belonging to the RECQ family are among the cancer suppressors linked to DNA repair. During the course of evolution, RECQ genes appear to have been amplified and diverged from a single copy of the RecQ gene in bacteria and yeast to five RECQ homologs in humans. The human RECQ proteins share many similar biochemical properties in vitro and are implicated in many common processes, suggesting they have overlapping functions in vivo. Yet these proteins are not redundant, as mutations in different RECQ proteins lead to different clinical syndromes. So far, BLM, WRN and RECQ4 have been associated with distinct clinical diseases: Bloom syndrome (BS), Werner syndrome (WS) and Rothmund-Thomson syndrome (RTS), respectively. Individuals with BS or RTS exhibit various physical and mental developmental abnormalities, while WS patients’ most striking phenotype is premature aging. Most importantly, all these patients, in particular BS patients, have a high risk of cancer predisposition. As a consequence, cancer is the primary cause of death for BS patients before the age of 30.
The various clinical features shown by individuals with RECQ-related diseases indicate that the human RECQ homologs have evolved to function in distinct pathways to protect the integrity of our genome and ensure proper development. A defect in one RECQ protein is sufficient to cause cell transformation and tumorigenesis, and this defect cannot be compensated by other RECQ proteins. Our long-term agenda is to dissect the functions of individual RECQ proteins in human cells, and these studies will allow us to compare the similarities and differences among the RECQ proteins. Through these comparisons we can then understand what aspects of genome maintenance and DNA metabolism are required for normal development and cancer prevention.