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This week we profile a recent publication in Nature Communications from Dr. Emily Chang
(pictured, second from left) the laboratory of Dr. Peter Stirling (right) at the Terry for Laboratory.

Can you provide a brief overview of your lab’s current research focus?

Our current focus is on understanding how cells faithfully replicate, repair, and segregate their DNA during cell division, and how cells respond to stresses that disrupt these processes. This process of genome stability maintenance involves many coordinated factors that together comprise one of the most important mechanisms of tumour suppression. We aim to understand genome stability mechanisms for at least two reasons. First, knowing the mechanisms that are disrupted in cancer will shed light on mutational processes driving cancer risk and progression. Second, many therapies elicit DNA damage, and understanding how cancer cells use genome stability maintenance factors to survive this stress will help us design better therapies.

What is the significance of the findings in this publication?

We found that a well-characterized DNA repair complex, called the MRN complex, had a new role in responding to DNA replication forks that have been blocked by collisions with the transcription machinery. These transcription-replication conflicts are likely to occur more frequently in cancer cells, and represent a major source of ongoing stress in many tumours. Our study began with a genetic screen in yeast, which identified many new factors, including the MRN complex, that are required for survival in cells with high levels of replication-transcription conflicts. We then moved into human cell lines and found that, while the MRN complex contains a nuclease activity, our data suggest that a non-nucleolytic scaffolding role of the complex is important to promote the recruitment of downstream repair factors to conflicts during replication. These findings open up new prospects to understand how DNA repair factors are recruited to replication forks to handle endogenous stresses.

What are the next steps for this research?

Our focus now is two-fold. First, we are continuing mechanistic studies to build a richer understanding of the complete pathway from sensing of a transcription-replication conflict, to its resolution by helicase or nucleolytic activities. Second, we are moving to assess the frequency of these conflicts in primary samples from both normal and cancerous tissues. Together this will further define the molecular choreography that occurs to resolve transcription-replication conflicts, and link these findings to observations in the context of human tissues.

This work was funded by:

This work was funded by the Canadian Institutes of Health Research and the Canadian Cancer Society.

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