On February 15, 2022 LUMICKS, a leading life science tools company that develops equipment for dynamic single-molecule and cell avidity analysis, reported that its innovative C-Trap technology was utilized in important new research designed to understand the function of a key protein involved in double-stranded break (DSB) repair (Press release, LUMICKS, FEB 15, 2022, View Source;utm_medium=rss&utm_campaign=simon-boulton-nature-paper-dna-repair [SID1234608124]). DSB repair is fundamental in maintaining the genome integrity and when compromised can lead to cancer predisposition.
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The research, published in Nature (December 22, 2021), focused on protein HELQ, and was titled "HELQ is a dual-function DSB repair enzyme modulated by RPA and RAD51". It was authored by Simon J. Boulton’s team from The Francis Crick Institute in London, Simon Powell’s team from Memorial Sloan Kettering and Weill-Cornell Medical in New York, and David Rueda’s group from Imperial College London and London Institute of Medical Sciences.
In their paper, the researchers disentangled the diversity of molecular mechanisms of HELQ. This revealed that HELQ is involved in many different branches of the DSB repair process and demonstrated how RPA and RAD51 differentially regulate its activity throughout the DNA repair process.
According to Dr. Boulton, "We show that HELQ possesses helicase activity and a previously unappreciated DNA strand annealing function are differentially regulated by RPA and RAD51. Using biochemistry analyses and dynamic single-molecule imaging, we established that RAD51 forms a complex with and strongly stimulates HELQ as it translocates during DNA unwinding. Conversely, RPA facilitates the annealing of complementary DNA strands."
In addition, the team noted, "Our study implicates HELQ in several distinct DSB repair pathways, including HR, SSA and MMEJ, casting light on its role in genome stability and tumor avoidance. These insights help us explain why HELQ loss confers genome instability, infertility and cancer predisposition."
Dr. Boulton added, "This paper is the culmination of nearly a decade’s work trying to understand how HELQ functions in DNA repair."
Key to this understanding was the visualization of HELQ-induced unwinding through LUMICKS’ C-Trap technology with Bluelake operating software, while the python package Pylake was used to analyze the data and reveal the unique insights of dynamic single-molecule experiments.
"Understanding this protein’s function – how it interacts with other proteins and its role in mediating DSB repair – can ultimately help us in understanding mechanisms of genome stability and cancer avoidance," said LUMICKS Chief Scientific Officer, Dr. Andrea Candelli. "Ultimately, studies such as these can offer new and unexplored therapeutic strategies to target DSB vulnerabilities in cancer. We are very pleased that our innovative software played a crucial role in both collecting and analyzing these detailed experiments, conducted at the single-molecule level on HELQ."