Engelward lab

Why Study Homologous Recombination? Click here to learn more...

Research Areas in the Engelward Laboratory:

1. Developing New Tools for Studying Homologous Recombination

FYDR scheme

The first engineered mice that permit fluorescence detection of recombinant cells in somatic tissues.

Despite its central role in genome maintenance, until recently, it was not possible to study homologous recombination in most cell types of a mammal. Therefore, in this laboratory, we developed a novel approach for studying homologous recombination that is based on a transgenic reporter that is inserted into the mouse genome. Homologous recombination events at the reporter sequence can give rise to a fluorescent readout by reconstituting full length enhance yellow fluorescent protein (EYFP) coding sequence. These Fluorescent Yellow Direct Repeat (FYDR) 'recombomice' provide a new way to study homologous recombination and have been used in a variety of studies (Hendricks et al., 2003; Kovalchuk et al., 2004; Wiktor-Brown et al., 2006). Most recently, using the FYDR mice we learned that cells harboring sequence rearrangements accumulate with age, that recombination is an active repair pathway in the adult mammalian pancreas, and that recombinant cells can persist and clonally expand during aging (Wiktor-Brown, et al., 2006).

2. Understanding Natural Causes of Homologous Recombination


We have found that certain chemicals produced during inflammation are highly recombinogenic.

We are interested in identifying common human exposures that induce homologous recombination. Inflammation is an important risk factor for cancer. In fact, >10% of cancers world wide are associated with infectious diseases, many of which induce chronic inflammation. In studies of microbial cells, we found that homologous recombination is one of the most important DNA repair processes for preventing toxicity induced by reactive nitrogen species (see Spek et al., 2001 and Spek et al., 2002). Recently, we found that certain chemicals excreted by activated macrophages during inflammation are highly recombinogenic. These results suggest that inflammatory chemicals may be among the most recombinogenic exposures common to the human experience. The details of these results was published in Chemistry & Biology (Kiziltepe et al., 2005).

3. Understanding the Underlying Causes of Homologous Recombination


We have found that a single acute exposure to a cancer chemotherapeutic induces recombination in distantly descendant cells and in their neighbors.

In our studies of conditions that stimulate homologous recombination, we learned that recombination events are not only directly induced by exposure to DNA damaging agents, but they can be induced through two other interesting mechanisms: persistent effects and bystander effects. Persistent genomic instability is defined as a persistently increased risk of de novo mutations, or in this case, recombination events. Bystander effects describe a situation in which a cell that has been exposed to a DNA damaging agent can induce DNA damage in a neighboring unexposed cell. It has long been known that radiation induces both persistent and bystander effects. In this laboratory, we have shown that exposure to chemical used during chemotherpay induces both persisten and bystander effects,, thus demonstrating that these effects are not exclusive to radiation, but rather are likely to be a more general response. Furthermore, we have shown that these two responses are related: cells that have a persistent instability phenotype can induce a bystander effect in neighboring undamaged cells (Rugo et al.)

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