Question!
In a healthy, normal body, cellular replication is carefully orchestrated to fit our developmental needs. Our cells have an intricate set of molecular checks and balances that maintain proper functionality. When mutations occur that allow cells to replicate unchecked, and our defense mechanisms against those mutations fail, we suffer from the general disease of cancer, which can take many forms. Being that it’s the second leading cause of death in the United States (NCHS, 2015), much research is conducted aimed at discovering the causes, treatments, and prevention of cancer. Since the replication of cancer cells obviously requires replication of the DNA, does this mean that the origin of replication could be a target for cancer treatment in humans?
Current consensus
Recent research has linked origin of replication-specific mutations to a number of common cancers. There are at least two broad categories of origin of replication (OR) mutations that have been linked to cancer: an abnormal increase in OR activity (Di Paoloa et al., 2006; Tao et al., 2001), or activation of normally silent ORs (Openheim and Martin, 1978; Valenzuela et al., 2012). Studying the relationship between ORs and cancer is difficult as an estimated 50,000 ORs are activated during cell replication (Mechali, 2008). Nonetheless, researchers have made great strides in determining the significant role of specific malfunctioning ORs in ovarian and cervical cancer as well as lymphoma (Mesner et al., 2011; Valenzuela et al., 2012).
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There is still a significant amount of research needed to further our understanding of the roles of specific ORs in cancer. However, with increasing knowledge comes the increased ability to make early prognoses. Knowing which OR mutation is associated with certain types of cancers can help in early screening and prognoses (Evertts and Coller, 2012). This can also lead to more precise forms of treatment. Current treatment of cancer involves radiation and chemotherapies, which are aimed at damaging the DNA of cancer cells. Unfortunately, treatments are not cancer-specific and normal cells are also affected by these highly toxic compounds. With increased awareness of the specific mutations in ORs associated with cancer, more precise therapeutics can be utilized to only combat the cancerous cells through either inhibition of the specific OR or a reduction in its activity (Boyer et al., 2016).
Question!
You have seen the background information and some of the ways that scientists study the origin of replication in human disease--and some of the challenges. Knowing what you know now, do you think that the origin of replication should be a research priority in a real-world situation of limited funding?
Current consensus
Research on replication origins and how they impact human health is taking place at the Cold Spring Harbor Laboratory based out of Cold Spring Harbor, NY. The laboratory has research programs in cancer, neuroscience, plant biology, quantitative biology and bioinformatics and genomics. The research on the origin of replication is primarily focused on understanding the features of DNA replication to also help better understand how errors in this process can result in genome instability, a hallmark of cancer cells. The research performed at this laboratory is also reported from the Institute of Human Genetics, a major unit of the National Center for Scientific Research based out of Montpellier, France (Bell et al., 2013).
Additional research is being funded and performed by the University of Nottingham in the UK. This research focuses on life without DNA replication origins by examining the possible consequences of having to use an alternative mechanism of DNA replication. This cannot take place in humans, but the study focuses on Haloferax volcanii because its rapid growth after replication origins are removed parallels that of cancer (Hawkins et al. 2013 Nature 503, 544-7).
Additional research is being funded and performed by the University of Nottingham in the UK. This research focuses on life without DNA replication origins by examining the possible consequences of having to use an alternative mechanism of DNA replication. This cannot take place in humans, but the study focuses on Haloferax volcanii because its rapid growth after replication origins are removed parallels that of cancer (Hawkins et al. 2013 Nature 503, 544-7).