The Laboratory, headed by Dr. Huilin Zhou, is interested in understanding how cells sense and respond to damages to their genome. Proper DNA damage response is necessary to ensure faithful duplication and segregation of the genome during each cell division. We study the regulation and functions of the DNA damage checkpoint, which has a central role in regulating the DNA damage response and is conserved from yeast to human. Inherited mutations to many human DNA damage checkpoint genes cause cancer-prone genome instability syndromes, aging and many other diseases. A wide range of experimental approaches including yeast genetics, protein biochemistry, molecular and cell biology, and state-of-the-art quantitative proteomics are used to address the following questions.

How do cells initiate a checkpoint response following DNA damage? The DNA damage checkpoint has a remarkable ability to both detect a single DNA break in the genome and respond to a wide spectrum of different DNA lesions that cells frequently encounter. We are interested in understanding how different DNA lesions are recognized, processed and amplified into signals to activate the DNA damage checkpoint, and how this critical process is coupled to the progression of cell division to prevent accumulation of mutations.

How do the DNA damage checkpoint kinases contribute to genome maintenance?Mutations to the ATR/ATM family protein kinases in the DNA damage checkpoint cause many types of genome instabilities, including chromosomal translocation, deletion and aneuploidy, which are the hallmarks of cancers. This is likely attributed to the loss of coordination between different nuclear processes such as DNA replication and repair. We are interested in understanding how these kinases orchestrate multiple nuclear processes to maintain genome integrity. To this end, we have pioneered the development and application of quantitative phospho-proteomics to identify their substrates and are studying their functions in detail. Our long-term objective is to understand how genome instabilities arise and how new insights could be used to develop innovative approaches for cancer detection and therapy.

Proteomic Biology