Breakthrough in understanding Warsaw breakage syndrome

September 4, 2018, Tokyo Metropolitan University
Chromosomal aberrations induced by exogenous DNA damage in DDX11 defective cells. Credit: Takuya Abe

Researchers from Tokyo Metropolitan University and the FIRC Institute of Molecular Oncology (IFOM) in Italy have uncovered a previously unknown function of the DDX11 helicase enzyme. Mutations in the gene, which codes for DDX11, are known to be implicated in Warsaw breakage syndrome. They showed that DDX11 plays an important role in DNA repair, and functions as a backup to the Fanconi anemia (FA) pathway, whose malfunction is associated with another life-debilitating condition.

DNA plays a central role in the biological function of the cell, but it is constantly being damaged, both spontaneously and through environmental factors. Failure to repair these lesions can lead to malignant tumors or cancer. Understanding how it is repaired is of the utmost importance; pioneering work on the subject was recognized with the 2015 Nobel Prize for Chemistry.

Warsaw breakage syndrome (WABS) is a genetic disorder. Afflicted individuals suffer from mild to severe intellectual disability and growth impairment, amongst other potential abnormalities. It was known that mutations in the DDX11 gene in Chromosome 12 in the human genome and the enzyme it codes for, the DDX11 helicase, were responsible for the onset of WABS, yet the mechanism by which DDX11 acted remained unclear. Thus, a collaboration led by Dr. Dana Branzei of IFOM, Italy and Prof. Kouji Hirota of Tokyo Metropolitan University set out to investigate the role played by DDX11 using avian cells, particularly noting similarities in the cells of WABS patients to those of Fanconi Anemia (FA).

What they found was that DDX11 played a vital role in DNA repair, acting together with the 9-1-1 checkpoint complex protein, which checks the integrity of DNA strands after replication. In doing so, DDX11 is critical in the repair of a wide-range of bulky lesions and also serves as a backup to the so-called FA pathway, specialized in the repair of interstrand crosslinks (ICLs), a harmful type of lesion that can lead to cell death and developmental problems. This finding explains the apparent similarity between WABS and FA cells exposed to ICLs, which caused WABS to be classified as a FA-like disorder. The researchers also discovered that DDX11 is involved in immunoglobulin-variable gene diversification, a key mechanism in the healthy function and adaptability of a healthy immune system. As immunoglobulin-variable gene diversification is induced by abasic sites, the most common endogenous lesion in mammalian cells, one implication is that DDX11 and 9-1-1 promote DNA damage tolerance of abasic sites, a finding that potentially explains the essential role of DDX11 and its similarity with 9-1-1 during development.

Besides shedding light on the mechanism underlying WABS, the study advances our understanding of the biological mechanisms behind genomic stability and how disorders arise at the cellular level. These results have profound medical significance for several conditions, including cancer and developmental disorders associated with DNA deficiency.

Explore further: RUNX proteins act as regulators in DNA repair, study finds

More information: Takuya Abe et al, Warsaw breakage syndrome DDX11 helicase acts jointly with RAD17 in the repair of bulky lesions and replication through abasic sites, Proceedings of the National Academy of Sciences (2018). DOI: 10.1073/pnas.1803110115

Related Stories

RUNX proteins act as regulators in DNA repair, study finds

August 15, 2018
A study by researchers from the Cancer Science Institute of Singapore (CSI Singapore) at the National University of Singapore has revealed that RUNX proteins are integral to efficient DNA repair via the Fanconi Anemia (FA) ...

Study identifies new gene mutation associated with defective DNA repair and Fanconi anemia

July 10, 2017
Fanconi anemia is a rare genetic disease characterized by hematologic symptoms that include low platelet count and unusually large red blood cells. Mutations in nearly 20 genes have been identified as causative for Fanconi ...

Artificial gene defect reveals target to fight genetic disease

June 12, 2018
Fanconi anemia (FA) is caused by defective genes for DNA-repair leading to bone marrow failure, developmental abnormalities and increased cancer risk. Using genome-wide genetic approaches, researchers at CeMM systematically ...

Recommended for you

Progress in genetic testing of embryos stokes fears of designer babies

November 16, 2018
Recent announcements by two biotechnology companies have stoked fears that designer babies could soon be an option for those who can afford to pick and choose which features they want for their offspring. The companies, MyOme ...

Gene editing possible for kidney disease

November 16, 2018
For the first time scientists have identified how to halt kidney disease in a life-limiting genetic condition, which may pave the way for personalised treatment in the future.

DICE: Immune cell atlas goes live

November 15, 2018
Compare any two people's DNA and you will find millions of points where their genetic codes differ. Now, scientists at La Jolla Institute for Immunology (LJI) are sharing a trove of data that will be critical for deciphering ...

Ashkenazi Jewish founder mutation identified for Leigh Syndrome

November 15, 2018
Over 30 years ago, Marsha and Allen Barnett lost their sons to a puzzling childhood disease that relentlessly attacked their nervous systems and sapped their energy. After five-year-old Chuckie died suddenly in 1981, doctors ...

Drug candidate may recover vocal abilities lost to ADNP syndrome

November 15, 2018
Activity-dependent neuroprotective protein syndrome (ADNP syndrome) is a rare genetic condition that causes developmental delays, intellectual disability and autism spectrum disorder symptoms in thousands of children worldwide. ...

The puzzle of a mutated gene lurking behind many Parkinson's cases

November 15, 2018
Genetic mutations affecting a single gene play an outsized role in Parkinson's disease. The mutations are generally responsible for the mass die-off of a set of dopamine-secreting, or dopaminergic, nerve cells in the brain ...

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.