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Distinguished Lecture Series

"Preservation of genomic integrity in somatic and embryonic stem cells”

The Stambrook lab has had a long-standing interest in genomic architecture and the mechanisms by which genomic integrity is preserved. In early studies, he investigated the timing of ribosomal DNA replication within the S-phase and demonstrated the heterogeneity of the repeating DNA units that encode 5S ribosomal RNA. His lab, in collaboration with Jay Tischfield, was the first to produce a mouse knockout of an autosomal reporter gene that allowed the measurement of somatic mutation frequency in vivo. The in vivo frequency of somatic mutation at a given locus is in the range of 10-4 with many of the mutagenic events at heterozygous loci caused by loss of heterozygosity (LOH) as a consequence of mitotic recombination. This observation led to a broader question and the proposition that we have been testing. If the very high mutation frequency observed in somatic cells were similarly high in germ cells, survival of any species would be unsustainable. We have therefore argued that germ cells must have mechanisms to protect the integrity of their genomes that are beyond those found in somatic cells. Using mouse embryonic stem (ES) cells as surrogates for germ cells, we have identified at least three such mechanisms that reduce the prevalence of mutations in ES cell populations.

About Dr. Stambrook

The long-term focus of my research has been to better understand the underlying regulatory controls for preserving genomic integrity, particularly in relation to embryonic stem cell self-renewal and maintenance of pluripotency. Although my interest in mutagenesis and genomic instability persists, my focus has evolved into the underlying mechanisms that give rise to cancer, particularly squamous cell carcinoma of the head and neck. In my early work, I showed that the temporal sequence of DNA replication can change during embryonic development in a vertebrate. I later demonstrated that the repeating units of 5S DNA were heterogeneous in size and sequence and subsequently my lab was the first to visualize replicating DNA from cultured mammalian cells. This work evolved into a knockout mouse model that we developed demonstrating that somatic in vivo mutation frequencies are extraordinarily high and that the predominant mutagenic pathway at heterozygous loci is loss of heterozygosity (LOH) mediated by mitotic recombination. Such a high mutation frequency in germ cells would be unsustainable for a species, which led to the hypothesis that embryonic stem (ES) cells, as surrogates for germ cells, must have multiple mechanisms by which they preserve their genomic integrity. We then showed that mouse ES cells have mutation rates, including LOH, two orders of magnitude lower than isogenic somatic cells. In addition, signaling pathways leading to a G1/S phase arrest that are triggered by double strand DNA breaks and which are downstream of ATM are compromised, leading to death of cells with damaged DNA. These cells are capable of double strand break repair, but preferentially utilize high fidelity homology-mediated repair rather than error-prone non-homologous end-joining that is predominantly used by somatic cells. My work has also focused on cellular responses to DNA damage, and regulation of the cell cycle. To this end, we have produced several mouse knockout and knockin mouse models to help establish physiological consequences of disrupting these pathways. We are now performing whole genome sequencing of head and neck tumors and glioblastomas to use DNA rearrangements as a minimally invasive biomarker for recurrence. In addition to the basic research focus of my lab, I have historically had collaborative translational projects with oncologists and surgeons. Some of our work on HSVtk and gancyclovir treatment and consequent bystander effect evolved into clinical trials. I have been particularly interested and involved in graduate and postdoctoral training, and in that context I have, for 27 years directed an NIH-funded T32 training grant entitled “Environmental Carcinogenesis and Mutagenesis” that was recently renewed

2016-2017 Series Information

 VCR Distinguished Lecture Series Event Schedule

 

stambrook lecture series information

Date: Thursday, February 16, 2017
Time: 12 to 1 pm
Location: Freeman Auditorium, 930 Madison Avenue, 3rd Floor

Last Published: Feb 2, 2017