Interview with Professor Haiying Hang
By Joy Fleming July, 2010
1. What is the research focus of your laboratory? Tumor development mechanisms derived from genetic defects in genes involved in cell cycle control and/or DNA damage repair.
2. What are the main breakthroughs/achievements your research group has made in the last three years? We found that Rad9 and Rad1 prevented tumor development through stabilizing the genome, that Rad9 plays a direct role in DNA mismatch damage repair through physical interaction with the key mismatch repair protein MLH1, and that Rad1 is able to function not only as part of the 9-1-1 complex (Rad9-Rad1-Hus1), but also independently of Rad9.
3. You’ve recently published your research in Molecular Cancer. Where does this paper fit into the story of the work your lab is doing? . This paper suggests that Rad1 has independent function(s) beyond its roles through the 9-1-1 complex. Many researchers in the DNA repair and cell cycle control field believe that Rad9, Rad1 and Hus1 play roles only through the 9-1-1 protein complex, but this belief is not backed up by unequivocal experimental evidence.
4. What are the major findings? Although deletion of Rad1 enhances skin tumor development in mice to a similar extent as Rad9 deletions, the molecular mechanism of skin tumor development in Rad1-deleted mice is different. Rad9 deletion activates p53 activities: increased p21 expression, dramatically slows down cell proliferation and elevates apoptosis, while deletion of Rad1 does not. Deletion of either Rad9 or Rad1 increases levels of DNA damage.
5. Can you summarise the significance of your paper in layman’s terms? Rad9, Rad1 and Hus1 are evolutionarily conserved from yeast to humans. They are found to play roles in cell cycle checkpoint control and resistance to DNA damage. Together with Professor Tao Jiang’s group and the Pearl and Cho groups, we recently solved the structure of the 9-1-1 protein complex. Various other lines of biochemical evidence, including results from my research group, support that Rad9, Rad1 and Hus1 forms a 9-1-1 heterotrimer. Most people in the field therefore believe that these three proteins function only through the 9-1-1 complex. In this paper, we’ve shown for the first time that Rad1 has functions that are independent of Rad9, thus suggesting that the 9-1-1 form is not the only form in which Rad1 works. The 9-1-1 complex probably works in some areas and Rad1 probably functions independently in some other cellular activities since Rad9, Rad1 and Hus1 play roles in multiple cellular activities.
6. What’s the next step in this work and do you have a strategy for doing that? We will generate Rad1+/-, Rad9+/-, Rad1+/- plus Rad9+/-, and Rad1+/+ plus Rad9+/+ mice with the same genetic background, and compare their skin tumor development, skin cell proliferation, p53 levels, p53 phosphorylation status, p21 levels and apoptosis levels. We hope to reveal the molecular roles of Rad1 and Rad9 that underly mouse skin tumor development through these experiments.
7. Where do you see your research leading in the future? Rad9, Rad1 and Hus1 are known to play roles in cell cycle checkpoint and DNA repair. They play these roles through both known and as yet unknown pathways. We want to investigate how many pathways are involved and why there is a need for multiple pathways.
8. What are the implications of your research for society? Defects in cell cycle control and DNA repair are two major mechanisms in tumor development. Dissecting how exactly defects arise and finding ways to intervene will help in the development of more efficient tumor therapies.
9. What else is your lab working on now? We are developing technologies for functionalizing and/or optimizing mature proteins and newly designed proteins. We hope to generate antibodies, peptides and enzymes that can be applied in therapy, diagnostics and other areas. Specifically, we are developing in vitro protein evolution processes that mimic biological evolution processes, but offer much faster rates of gene mutation and functional selection.
10. How did you get into this area of research? Major industries have been built up from the knowledge obtained through the study of physics and chemistry. However, discoveries in biology have not yet led to the development of a major industry. Biological systems are much more complicated in form and at the molecular level. Bioparts such as proteins cannot be simply designed and manufactured like mechanical, electronic and optical parts. In nature, new proteins (genes) are functionalized over a very long time through the evolutionary process (mutation plus selection). These processes can be mimicked in a laboratory through so-called ‘in vitro evolution’, allowing designed proteins to be functionalized through a much faster process of mutation and selection.
11. Which of your professional achievements brings you the most satisfaction? The discovery that Rad9 is a key protein in DNA mismatch damage repair.
12. What are the big issues/outstanding problems that have to be addressed in your field? How do the many proteins/genes involved in cell cycle control and DNA repair coordinate their roles to maintain genomic integrity?