Cell sub-journal: DNA repair defects may lead to BRCA-related cancers

According to a new study from Weill Cornell Medical College, individuals who inherit a mutated copy of the BRCA1 gene can have error-prone DNA replication and repair that can lead to mutations and cancer
.
This finding has potential implications
for preventing cancer development in patients with these mutations.

The study provides new insights
into why individuals who inherit a mutation in one copy of the BRCA1 gene tend to develop mutations in their remaining normal BRCA1 gene copy, laying the groundwork for tumor development.
When these people's cells are stressed, replication of the normal BRCA1 gene stops because highly repetitive DNA sequences in the gene create physical barriers
to the mechanisms that replicate DNA.
To repair stalls, an error-prone DNA repair mechanism comes into play
.

Dr Jeannine Gerhardt, senior author of the study, said: "We have identified some of the first steps
in cancer development in people who carry inherited BRCA1 mutations.
" Dr.
Jeannine Gerhardt is an assistant professor of stem cell biology in obstetrics and gynecologic and a professor
at the Ronald O.
Perelman and Claudia Cohen Center for Reproductive Medicine at Weill Cornell Medical College.

The BRCA1 gene encodes an important DNA repair protein, explains Dr.
Madhura Deshpande, lead author of the study and a research associate at the Center for Reproductive Medicine at Weill Cornell Medical School
.
A person who inherits one mutant and one normal copy produces about half
the cost of this DNA repair protein as someone who has two normal copies, Desshpander said.

To understand why the remaining functional BRCA1 gene copies are also frequently mutated, the team studied DNA replication
in human embryonic stem cells and human breast epithelial cells with a mutated copy of the BRCA1 gene.
Human embryonic stem cells were grown at the Center for Reproductive Medicine by Dr.
Nikka Zaninovich and Dr.
Zev Rosenvaks
.
They exposed the cells to a chemical that mimics the stress of the environment on the cells
.
They found that when the DNA in these cells broke down into two strands to replicate the DNA for each new cell, the mechanism of replicating the DNA was suspended
in the BRCA1 gene due to the duplication of the DNA sequence of the BRCA1 gene.
The team also demonstrated for the first time that the BRCA gene is a fragile site that is prone to rupture
.
Dr.
Desshpande explained that because only half of the BRCA1 protein in these cells can repair breaks, the cells turned to a more error-prone backup DNA repair mechanism called microhomology-mediated break-induced replication (MMBIR).

The team also examined tumor cells
from women with breast cancer linked to mutations in the BRCA1 gene.
They found mutations in the BRCA1 and BRCA2 genes, such as deletions and insertions, most likely caused by errors in the MMBIR process
.

Dr.
Deshpande said: "We are currently interested in finding other error-prone repair mechanisms
that may lead to genomic instability and mutations in these cells.
" Dr.
Gerhart said the team was also looking for real-life environmental stressors
that cause replication problems and DNA repair defects in BRCA1-related breast cancer.

The team is also working to develop strategies to prevent the use of error-prone DNA repair mechanisms
in women with BRCA1 gene mutations.
For example, they are testing the protective effects
of dietary compounds linked to reduced breast cancer risk in BRCA1 mutation carriers.
If they succeed, they may be able to identify drugs or other interventions that can prevent cancer in women with BRCA1 gene mutations and offer alternatives to existing invasive preventive measures, such as preemptive mastectomy or oophorectomy
.

"I believe we can intervene and find compounds that prevent patients carrying inherited BRCA1 mutations from accumulating cancer-causing mutations," Dr.
Gerhart said
.