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Dheva Setiaputra

2018-07-19

Dheva has been a post-doctoral fellow in Dan Durocher’s lab for just over a year. In a group of cell biologists, Dheva is a proud biochemist. Dheva earned his PhD in Vancouver at the University of British Colombia where he worked to solve the structure of protein complexes using electron microscopy. He came to Dan’s lab because he loves purifying proteins and determining their structure but he wanted to extend his knowledge to be able to design novel types of experiments. One aspect that drew him to Dan’s lab is that Dan is unafraid to take on people with other expertise and has a wealth of knowledge in techniques that Dheva wanted to learn.

Dheva Setiaputra
Dheva Setiaputra

The main interest in the Durocher lab is to understand how cells decide to repair double stranded breaks through either homologous or non-homologous recombination. Homologous recombination (HR) is a mechanism that ensures repair of the correct nucleotide sequence through the exchange of strands of DNA with the identical sequence from a sister chromosome (somatic cells all contain a pair of each chromosome, plus the sex chromosomes). On the other hand, non-homologous end joining (NHEJ) recombination is achieved by using a non-identical strand of DNA to fix the break, which, while allowing for repair, introduces changes in the nucleotide sequence. If the break is within a coding region of a gene, this may inactivate or mutate the gene. If outside the coding regions, such error-prone repair may still affect gene expression. The two pathways antagonize each other which is important, for example, with the subclass of breast and ovarian cancers that have mutations in BRCA1/2. When cells have mutations in one of these genes the cells lose their ability to employ homologous recombination. Interestingly, if the NHEJ pathway is blocked in BRCA1/2 mutant cells, homologous recombination is reactivated.

There is a recent class of drugs that act as poly(ADP-ribose) polymerase (PARP) inhibitors.  Cells that are incapable of homologous recombination are highly sensitive to PARP inhibition. For example, tumour cells lacking functional BRCA1 or BRCA2 are far more susceptible to PARP inhibitors than normal cells. Unfortunately, some cancers develop resistance very quickly through inactivation of the NHEJ pathway. The Durocher lab is trying to figure out how these factors antagonize each other and why knocking out NEHJ repair can reactivate homologous recombination, even in the absence of BRCA1. The lab makes heavy use of genome-wide screens and the results of one of these led to the recent discovery of a new complex comprised of largely uncharacterized proteins called the Shieldin complex that act to protect the newly exposed ends of DNA breaks from attack from nuclease (see article on Salomé Adam). Currently, the group is characterizing the complex to test whether knocking out any individual member of the complex renders BRCA1 mutant cells resistant to PARP inhibition. Dheva’s role is to figure out how the complex assembles, the functional roles that the complex may have and what biochemical activity it exhibits. He approaches these questions by purifying each component, performing assays and assessing which regions of the protein are required for interactions.

Dheva’s biggest challenge was adapting to a lab where the focus was mostly cell biological. As a biochemist he learnt a lot of techniques and how to use a number of machines whereas in a cell biology context the emphasis is on learning about the actual biological behaviours of the cells. He also changed fields to DNA repair from chromatin biology which required a lot of reading and catching up with the literature, not to mention a whole new world of acronyms. What helped him the most in the transition was his fascination with new techniques and the joy of new knowledge. Moreover, when working in Dan’s lab there are lots of resources and expertise, which is liberating for Dheva because if he wants to do something, he doesn’t need to go far to make it happen. Nothing seems impossible. 

 

By Sophie Lily Polan

          
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