Cancer comes in many forms, but it is characterised by cells rapidly dividing out of control. Chemotherapy refers to a group of drugs which use a range of mechanisms to try and block the cells from dividing. One group of chemotherapy drugs, commonly used to treat chronic and acute leukemia, lymphoma and Hodgkin disease among others, works by targeting the genetic material inside cancer cells linking together the DNA strands, thereby stopping the cell copying its genetic material so the cell dies. However, cancer cells have a mechanism for dealing with this, by triggering systems in the cell that can repair the DNA damage, reversing the impact of chemotherapy.
A group of scientists from Cancer Research UK have been using Diamond to study the structure of a protein called FANCL which is known to play a role in initiating the DNA repair process. Understanding how this protein functions could help make this form of chemotherapy more effective. Their work has been published in the journal Nature Structural and Molecular Biology.
Fanconi anemia (FA) is a disorder associated with a range of skeletal abnormalities, microcephaly and bone marrow failure, as well as a predisposition to several cancers. The FA pathway is activated in response to DNA damage, such as that caused by chemotherapy drugs. At the heart of the FA pathway is the FA core complex, which triggers the repair process.
Previous studies have identified the proteins within the core complex that are required for the trigger, but structural information on the proteins involved has been lacking. By determining the crystal structure of the FANCL catalytic subunit, the group have shown that the structure is fundamentally different to sequence-based predictions. As a result, they have achieved a complete molecular understanding of the cascade that initiates DNA repair.
Dr Helen Walden is the lead investigator at Cancer Research UK's London Research Institute.
"Our team has determined the structure of the engine in the cell's maintenance pack that if switched off would make cells much more responsive to chemotherapy. We have taken the first full atomic snapshot of a protein in this cell repair pathway, right at the very heart of the route by which cancer cells defend themselves against treatments which are intended to destroy them. By blocking this repair ‘ignition switch’ it may be possible to boost traditional treatments. As such, it's a drug target.”
Dr Helen Walden, Cancer Research UK
The structure of the catalytic subunit FANCL of the Fanconi anemia core complex, Cole, A., Lewis, L., & Walden, H. (2010). Nature Structural & Molecular Biology, 17 (3), 294-298
Diamond Light Source is the UK's national synchrotron science facility, located at the Harwell Science and Innovation Campus in Oxfordshire.
Copyright © 2018 Diamond Light Source
Diamond Light Source Ltd
Harwell Science & Innovation Campus