2 new genes have been identified in which mutations can interfere with a cell’s ability to remove misplaced links between DNA strands, and, as a result, cause a rare genetic disorder known as Fanconi anemia. These discoveries offer new insight on a repair process critical to maintaining certain tissues and preventing cancer.
Dividing cells are prone to errors, and so they must be prepared to summon sophisticated emergency systems to deal with potential damage. One type of division-derailing mishap can occur when assault by certain chemicals causes 2 strands of DNA to permanently connect when they shouldn’t, in what scientists call interstrand crosslinks (ICLs). Properly fixing these crosslinks is crucial to preventing cancer, maintaining tissues, and fertility.
To better understand how a cell finds and fixes these misplaced crosslinks, researchers at The Rockefeller University and their colleagues are examining the genomes of patients in whom the repair process is defective. “…we had two patients who each represented a sort of mystery: They had symptoms of Fanconi anemia, but no genetic cause yet identified,” says A/Prof Agata Smogorzewska, “Our investigation led us to discover a defective RAD51 protein in one patient, and a similarly dysfunctional protein UBE2T in the other.”
The genes that code for RAD51 and UBE2T contribute to a repair process known as interstrand crosslink repair, which fixes a misplaced attachment between 2 strands of DNA. Caused by chemical agents, including often used chemotherapies like cisplatin; chemicals called aldehydes that occur naturally within cells, and nitrous acid formed after eating nitrates, ICLs block the replication of DNA, making it impossible for cells to accurately copy their genomes as they divide. The ICL repair process uses multiple enzymes that cut away the connection between the DNA strands, freeing them up and allowing the cells to grow.
Defects in ICL repair pathway can produce Fanconi anemia symptoms: a predisposition to cancer, failure of the stem cells in bone marrow responsible for producing blood cells, infertility, as well as developmental defects.
In one patient they found mutations in 1 of 2 copies of the gene for RAD51, already known to be important for another DNA repair process, homologous recombination, in which a missing section of DNA is replaced using its sister strand as a template, and is thought to be used during the last step of ICL repair, after the crosslink has been cut. As only one copy of the RAD51 gene was partially defective, her cells could still perform homologous recombination, but not ICL repair. If both copies of RAD51, which is essential for life, had been defective, the girl would never have been born.
To show that the defective copy of the RAD51 gene was indeed responsible for her symptoms, the researchers genetically engineered the patient’s own cells to remove the defect, which restored their ability to fix ICLs.
In the UBE2T Fanconi study, though it was already known that UBE2T is involved in activating ICL repair, the discovery revealed the protein is an irreplaceable player in the pathway. “By identifying new disruptions to this repair pathway, we can better understand the mechanisms of an event that is crucial to every cell division – a process that occurs constantly within the human body throughout a lifetime,” Smogorzewska says. http://newswire.rockefeller.edu/2015/08/07/mutations-linked-to-genetic-disorders-shed-light-on-a-crucial-dna-repair-pathway/
Put to the test: To confirm that a defect in RAD51 interfered with cells’ ability to fix misplaced links between DNA strands, researchers treated patient cells with an agent to cause such links to form. The cells failed to repair them, producing broken chromosomes that fused with one another (red arrows).
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