Advisor: Prof. Mark Williams
First Job: MRC Career Development Fellow, Imperial College London (post-doc)
“DNA is a double-stranded helix of complementary base pairs, and many proteins are required to organize cellular DNA and read the genetic code,” says Chaurasiya. “I use optical tweezers to capture and stretch a single molecule of DNA in the presence of these proteins. They bind the DNA molecule and alter its structure, and measurements of these effects provide insight into the function of these proteins inside complex living systems.”
Chaurasiya says she chose Northeastern University for her Ph.D. specifically to do this particular kind of research.
“Mark has been an amazing advisor, one of those rare physicists who understands both the world and the people in it,” she says. “His explanations on seemingly intractable topics crystallize in a concise and elegant way, and I knew that joining his group would allow me to explore the biology questions I find important and interesting.” Chaurasiya’s thesis research has focused on replication of retroviruses and retrotransposons, which reproduce by copying their RNA genome into cellular DNA.
“In the paper I just submitted*, I used optical tweezers to demonstrate and quantify the two biophysical mechanisms by which the human protein APOBEC3G (A3G) inhibits HIV replication.”
Chaurasiya explains that A3G is a protein present in the type of human cells susceptible to HIV, and it inhibits HIV replication in the absence of the viral infectivity factor, which is protein the virus evolved to counteract A3G.
“It has been well-established that A3G mutates viral DNA, which impairs viral replication. However, there is also strong evidence for an additional, unknown mechanism by which A3G inhibits HIV replication. Our collaborators have proposed the roadblock model as a hypothesis, in which A3G binds the HIV genome and blocks the HIV DNA polymerase, called reverse transcriptase, from making the virus’ DNA. However, because only about seven A3G molecules are inside the virus, the roadblock mechanism requires A3G to unbind from single-stranded nucleic acids very slowly. However, A3G is an enzyme that mutates the viral genome very quickly, which requires rapid on-off rates from single-stranded nucleic acids.”
Chaurasiya says she resolved these seemingly contradictory biophysical mechanisms by demonstrating that oligomerization transforms A3G from a fast enzyme to a slow nucleic acid binding protein. “This paper answered a very specific question: how does A3G work against HIV? But the biophysical mechanism we demonstrated could also be how other proteins similar to A3G regulate their enzymatic activity in order to inhibit retroviral replication in multiple ways. The relative strength of these two redundant mechanisms is probably optimized by the cell’s immune system for different responses to retroviruses and other threats to human health.”
Prof. Williams says he has no doubt that Chaurasiya’s accomplishments at Northeastern will have a very strong impact on the field of retrovirus replication, as well as in single molecule biophysics.
“Her work on A3G could only be done by someone with great experimental skills as well as the ability to work independently with several researchers from different fields, from theoretical biophysicists to virologists,” he says. “Kathy’s incredible work ethic, intelligence, instinct for research, and great communication skills have all combined to make her a stellar and accomplished researcher.”
*UPDATE: Chaurasiya’s paper was published in Nature Chemistry and highlighted in News and Views.
Kathy R. Chaurasiya, Micah J. McCauley, Wei Wang, Dominic F. Qualley, Tiyun Wu, Shingo Kitamura, Hylkje Geertsema, Denise S. B. Chan, Amber Hertz, Yasumasa Iwatani, Judith G. Levin, Karin Musier-Forsyth, Ioulia Rouzina and Mark C. Williams. Oligomerization transforms human APOBEC3G from an efficient enzyme to a slowly dissociating nucleic acid-binding protein. Nature Chemistry 6: 28-33 (2014).