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SVI researchers unlock Fanconi Anaemia signalling pathway

Posted: 19th December 2016

SVI researchers, in collaboration with scientists from the Francis Crick Institute in the UK, have, in a world first, been able to recapitulate in the test tube the defect that occurs in the disease Fanconi Anaemia.

Fanconi anaemia is a rare genetic disease that leads to blood disorders (including aplastic anemia and acute myeloid leukemia) at an average age of 7 years old and an increased predisposition to cancer in later years. Approximately 1 in 80,000 people are affected.

The disease is caused by mutations in any one of a number of genes called the FANC genes. These encode proteins that work together – as a complex – to repair damaged DNA. When DNA damage occurs in someone who carries a FANC mutation, it cannot be repaired, meaning that their risk of cancer is hundreds of times higher than in healthy people.

Published in Molecular Cell, the research describes how the group at SVI has been able to reconstitute the FANC complex in the test-tube. This has allowed them to determine how the proteins fit and function together and will be an optimal tool to enable them to screen for drugs to treat the disorder.

Lead author Dr Andrew Deans says, “We are constantly exposed to factors which damage our DNA – for example, UV light, cigarette smoke and certain chemicals. FANC proteins form a remarkable molecular machine that repairs this DNA damage.”

He says that the complexity of this machine, made up at least 10 proteins, has meant that reconstituting it in the test-tube has, until now, been impossible. This has slowed progress in understanding the disease because it hasn’t been possible to determine exactly how all the different FANC proteins collaborate to perform their DNA damage repair function.

Dr Deans says that one complication of treating people with Fanconi anaemia is that their cells are particularly sensitive to the toxic effects of chemotherapeutic drugs, meaning that when they get cancer, many of these drugs cannot be used.

“The only current treatments for the disease are bone marrow transplant, life-long surveillance for cancer and then limited options when cancer arises. Our system offers a way to screen for drugs that can be used to repair the original defect. In addition, because mutations that cause Fanconi anaemia are found in different places across many different genes, we can use our system to “personalise” the complex – specifically recreating a mutation that is found in a particular patient.”

“This discovery will help us identify how Fanconi anaemia arises, why the cancer predisposition occurs and will help us develop new treatments for people with the disease.”

“In addition, it offers the opportunity to understand better how currently available chemotherapeutics affect cancer cells and an opportunity to design more effective chemotherapeutic drugs,” said Dr Deans.

The work was published in the journal Molecular Cell, and was funded by the Fanconi Anaemia Research Fund and the Federal Government’s National Health and Medical Research Council (NHMRC), with support from Maddie Riewoldt’s Vision.

See Andrew describe his discovery here.

For more information please see: Genome stability