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Publications of the Week

ARID1A Regulates R-Loop Associated DNA Replication Stress

By April 26, 2021No Comments

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This week we profile a recent publication in PLOS Genetics from Shuhe Tsai
(front, center) in the laboratory of Dr. Peter Stirling (pictured, back right) at UBC.

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

My lab is focused on why cancer cells usually make more mistakes than normal cells when copying, repairing, or segregating the DNA that makes up their genomes. This genome instability is one reason why tumours can acquire a heterogeneous mixture of mutations that ultimately fuels disease progression and evolution. One aspect of our work is to discover new ways in which genes that are recurrently disrupted in cancer might contribute to this genome instability process.  At the same time, we are interested in how these genome-destabilizing changes in cancer cells might be targeted with anti-cancer therapies. 

What is the significance of the findings in this publication?

Working with our collaborator Dr. David Huntsman, an expert in ovarian and other gynecological malignancies, we embarked on a project to characterize the effects of a gene called ARID1A on genome maintenance. The ARID1A gene is lost in a wide variety of cancers, but is especially frequently lost in ovarian clear cell carcinoma, where about 50% of cases express no ARID1A at all. ARID1A is part of a large complex of proteins that together control how DNA is packaged and which genes are expressed. Through this activity ARID1A performs a broad range of functions within the cell, so its potential connections with genome stability are complex. In this study we report new observations that cells lacking ARID1A experience increased genome instability due to conflicts between DNA replication and transcription; two normal processes that occur on the same DNA template and need to be coordinated to avoid damage to the genome. We find that one of the ways in which ARID1A contributes to the prevention of transcription-replication conflicts is through its effects on another protein called Topoisomerase 2A (TOP2A). TOP2A normally relieves pressure that accumulates in our DNA due to processes like replication and transcription. In cells lacking ARID1A, TOP2A localizes to the wrong places in our DNA and some sites now become prone to the accumulation of abnormal structures that can lead to physical damage in the genome. This physical damage is a source of mutations that can contribute to the development and evolution of tumours. Given how frequently ARID1A is lost in some cancers, these data will impact our thinking on the types of stresses that are ongoing in tumours lacking ARID1A. We hope that additional research will reveal new ways in which the increased transcription-replication conflicts in ARID1A deficient cancers be targeted for therapy.

What are the next steps for this research?

We are following up on this research in a few directions. ARID1A is part of a multi-subunit complex called the BAF complex. We want to understand more about how physical interactions of the BAF complex change and might influence genome instability in cells lacking ARID1A. At the same time, we are identifying potential therapeutic vulnerabilities in cells lacking ARID1A and hope to integrate knowledge of these vulnerabilities with the new insights on the mechanisms to move toward better therapeutic targets for cancers that lack ARID1A. 

This work was funded by the Terry Fox Research Institute and the Canadian Institutes of Health Research.

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