Scientists have revealed a brand new function for one of the
first cancer genes ever discovered - the retinoblastoma gene - in a
finding that could open up exciting new approaches to
treatment.
The retinoblastoma gene is so called because mutations to it
cause a rare children's eye cancer of the same name, and is known
to play a central role in stopping healthy cells from dividing
uncontrollably.
Now the new study - jointly led by scientists at UCL (University
College London) and The Institute of Cancer Research, London - has
found that the gene also has another important function, in helping
to 'glue' severed strands of DNA back together.
The research suggests that existing drugs that exploit the
weaknesses of some cancers in repairing their DNA could be
effective against tumours with mutations to the retinoblastoma
gene.
Researchers found that mutations to the retinoblastoma gene or
RB1 - which are found in many cancers - prevent the effective
fixing of broken DNA strands. This results in chromosome
abnormalities which can lead to the development of tumours and
drive cancers to evolve into more aggressive forms.
Numerous common cancer types have RB1 mutations, including
hard-to-treat cancers such as triple-negative breast cancer, small
cell lung cancer, glioblastoma, and aggressive types of prostate
cancer.
Researchers deleted the RB1 gene from lab-grown human and mouse
cancer cells, and looked at a variety of measures that indicate
defective DNA repair. They found substantially more double-stranded
DNA breaks and chromosome abnormalities in cells that lacked RB1
than those where the gene was functional.
In another experiment, the researchers demonstrated that the RB1
protein attaches to two other protein called XRCC5 and XRCC6,
forming a cluster of molecules that mend broken strands of DNA.
RB1 was first discovered in the 1980s and has long been known to
have an important role in controlling cell division. It was
discovered through studies of the rare eye cancer retinoblastoma,
which in around half of cases is caused by inherited mutations to
the RB1 gene.
Dr Paul Huang of The Institute of Cancer Research in London,
said: "The retinoblastoma gene was one of the first cancer genes to
be discovered and is one of the best known of all, so it's very
exciting to have been able to identify a completely new function
for it.
"The retinoblastoma gene is famous for helping control cell
division, but we found that it has another important job in gluing
broken strands of DNA back together. Our research could have real
implications for cancer patients, because drugs that exploit
weaknesses in DNA repair already exist, and there is now a
rationale for testing them against cancers with retinoblastoma gene
mutations."
Professor Sibylle Mittnacht of the UCL Cancer Institute, said:
"We are very excited about this new discovery. Our work
demonstrates that loss of the retinoblastoma gene promotes major
defects in cancer DNA which drives the evolution to a more
aggressive and therapy resistant form in major cancers such as
breast and lung cancers. At the same time, this discovery points to
exciting prospects for new and more effective ways in which these
cancers can be treated."
The paper, Direct Involvement of Retinoblastoma Family Proteins in DNA Repair
by Non-homologous End-Joining, is published in Cell
Reports.