The human body is composed of billions of cells, yet every one of us begins as just a single cell. This means that countless cell divisions occur during a human lifetime. Each cell carries the full set of genes from mom and dad, so every time a cell divides, the genome must be accurately and completely duplicated. We call the process of duplicating genes during cell division "DNA replication."
When considering how many cell divisions occur in each of us and how complicated the process of DNA replication must be, it is not surprising that mistakes during DNA replication cause birth defects and cancer. Despite its fundamental importance for all life, we still know little about how DNA replication is controlled in humans. The Sansam laboratory is identifying the genes, molecules, and mechanisms that are needed to replicate our DNA. We expect that such knowledge will provide a clearer understanding of how a wide range of human diseases occur and ultimately will lead to the development of better treatments for diseases such as cancer.
Lucky for us, DNA replication is so important that even very simple organisms share most of the genes and mechanisms involved with humans. In fact, scientists continue to shed light on how human DNA replication occurs by studying single-cell organisms such as yeast. Of course our genomes are more complicated than yeast, and not surprisingly, humans and other vertebrates have a more elaborate mechanisms for regulating DNA replication. The Sansam laboratory uses two experimental systems to shed light on the process of DNA replication in humans and vertebrate animals. First, to directly study how DNA replication is generally replicated in people, we use human cells dividing in culture. Second, to understand how DNA replication is regulated during the multitude of cell divisions that occur in the developing embryo, we use a simple vertebrate animal called the zebrafish. The zebrafish is the preeminent "model" organism for studying vertebrate embryonic development because it has a complex genome like humans, shares most genes with people, and is highly accessible for observation and manipulation. Using human cell culture and zebrafish, we can understand the genes and fundamental principles of DNA replication both at the single cell level as well as in the context of a real embryo.
My laboratory is interested in how the human genome is replicated. Every time one of our cells divides, billions of base-pairs must be duplicated in the correct sequence and in coordination with other important processes in the nucleus such as gene expression and DNA repair. To ensure that the genome is completely and accurately duplicated during every round of cell division, our cells use complex regulatory systems that determine when and where different parts of the genome are copied. We are just beginning to understanding the mechanisms of this "replication program," but we already know that deregulation of DNA replication leads to cancer and birth defects. We expect that defining the general principles and specific mechanisms of DNA replication control will ultimately lead to better treatments for a number of different diseases including cancer.
To obtain both mechanistic and in vivo information, we study the DNA replication using cultured human cells and zebrafish embryos. Because the zebrafish embryo develops externally, it provides an outstanding opportunity to understand how the genome is properly replicated during the multitude of cell divisions that must occur during embryogenesis. Furthermore, zebrafish can be used for genetic experiments more easily and quickly than other vertebrates. We are currently studying how the DNA replication program adapts to the vast array of cellular changes that occur during embryonic development. We are also delineating the basic mechanisms of DNA replication control. We are studying a number of recently discovered DNA replication control genes that are found in all vertebrates, including fish and humans. We are particularly focused on a DNA replication control gene called TICRR, which we discovered through a genetic screen in zebrafish. This gene is of particular interest because we have shown that it is a pivotal component of the system that determines when and where DNA replication initiates throughout the genome.
1997 B.S., James Madison University, Harrisonburg, VA (summa cum laude)
2004 Ph.D., Vanderbilt University School of Medicine, Nashville, TN
2010 Postdoc, Laboratories of Nancy Hopkins and Jacqueline Lees, Massachusetts Institute of Technology
Honors and Awards
1997 Outstanding Student Award, Integrated Science and Technology Program, James Madison University
1997 Dan May Summer Research Scholarship in Cardiology, Vanderbilt University
1997-2004 Harold Sterling Vanderbilt Graduate Scholarship
2001-2004 NIH Ruth L. Kirschstein Predoctoral National Research Service Award
2004 Anna Fuller Postdoctoral Fellowship
2004-2010 NIH Ruth L. Kirschstein Postdoctoral National Research Service Award NIH/NIGMS
Joined OMRF Scientific Staff in 2010
Wittig KA, Sansam CG, Noble TD, Goins D, Sansam CL. The CRL4DTL E3 ligase induces degradation of the DNA replication initiation factor TICRR/TRESLIN specifically during S phase. Nucleic Acids Res, 2021 September, PMID: 34534348, PMCID: PMC8501952
Hulke ML, Siefert JC, Sansam CL, Koren A. Germline Structural Variations Are Preferential Sites of DNA Replication Timing Plasticity during Development. Genome Biol Evol, 2019 May, PMID: 31076752, PMCID: PMC6582765
Patel MM, Behar AR, Silasi R, Regmi G, Sansam CL, Keshari RS, Lupu F, Lupu C. Role of ADTRP (Androgen-Dependent Tissue Factor Pathway Inhibitor Regulating Protein) in Vascular Development and Function. J Am Heart Assoc 7:e010690, 2018 November, PMID: 30571485, PMCID: PMC6404433
Sansam CG, Goins D, Siefert JC, Clowdus EA, Sansam CL. Cyclin-dependent kinase regulates the length of S phase through TICRR/TRESLIN phosphorylation. Genes Dev. 2015 Mar 1;29(5):555-66. PMID: 25737283 PMCID: PMC4358407
Sansam CL, Cruz NM, Danielian PS, Amsterdam A, Lau ML, Hopkins N, Lees JA. A vertebrate gene, ticrr, is an essential checkpoint and replication regulator. Genes Dev. 2010 Jan 15;24(2):183-94. PMID: 20080954 PMCID: PMC2807353
Dawson TR, Sansam CL, Emeson RB. Structure and sequence determinants required for the RNA editing of ADAR2 substrates. J Biol Chem. 2004 Feb 6;279(6):4941-51. PMID: 14660658