Scientists uncover the structure of a protein complex linked with breast and ovarian cancer risk

January 11, 2017, The Francis Crick Institute
Scientists uncover the structure of a protein complex linked with breast and ovarian cancer risk
Molecular scissors: in the background are DNA-damage foci, each red blob represents a single double-stranded break site in the genome. Credit: The Francis Crick Institute

Scientists at the Francis Crick Institute have described the molecular structure of a key tumour suppressor protein and provided insights into its role in cells.

BRCA1 is a human gene which produces the tumour suppressor protein of the same name. Mutations in BRCA1 can result in a 65-75% lifetime probability of developing breast cancer, and members of families at high risk of can be screened for mutations in the BRCA1 and related BRCA2 genes.

The BRCA1 protein has a key protective role in DNA repair and so helps to maintain genetic stability.

Mutations in the BRCA1 gene which result in insufficient or defective production of the BRCA1 protein will inhibit DNA repair and lead to genetic instability. This increases the likelihood of cancer-causing mutations.

The BRCA1 protein functions in interaction with three protein complexes (BRCA1-A, BRCA1-B and BRCA1-C).

Scientists at the Francis Crick Institute have described the of BRCA1-A and provided insights into its role in deubiquitination, an essential process involved in modulating DNA repair.

The scientists used a range of cutting-edge techniques, including , mass spectrometry and biochemical analysis. Electron microscopy was used to define the overall shape of the protein complex, but this was not sufficient to pin-point the exact locations of the individual molecular components.

A combination of native and was then used to provide the extra information required to triangulate the location of the components.

In the longer term, it is hoped that a more detailed understanding of the structure and function of the complex might inform efforts to develop inhibitors of the BRCA1-A and linked complexes which might be clinically useful.

Steve Smerdon, Group Leader at the Francis Crick and final author on the paper, said: "The structure, albeit at low resolution, is really the first structural glimpse of any of the major BRCA1 complexes. In a way, the size and complexity is somewhat surprising since the reaction it catalyses is relatively simple: the cleavage of a single bond between two linked ubiquitins. The structure now suggests how the overall architecture might act to stabilise interactions with ubiquitin chains. More importantly it also indicates how interaction with BRCA1 itself might regulate its activity."

The paper, Three-dimensional architecture of the human BRCA1-A histone deubiquitinase core complex, is published in Cell Reports.

Explore further: Research explains the role of the gene BRCA1 in DNA repair

More information: Otto J.P. Kyrieleis et al. Three-Dimensional Architecture of the Human BRCA1-A Histone Deubiquitinase Core Complex, Cell Reports (2016). DOI: 10.1016/j.celrep.2016.11.063

Related Stories

Research explains the role of the gene BRCA1 in DNA repair

May 30, 2016
Scientists at the University of Birmingham are a step closer to understanding the role of the gene BRCA1. Changes in this gene are associated with a high risk of developing breast and ovarian cancer.

BRCA1 mutations in breast and ovarian cancer can predict treatment resistance

July 25, 2016
Mutations in the BRCA1 gene are one of the most common risk factors for breast and ovarian cancers. Although tumors that harbor BRCA1 mutations initially respond well to cancer treatments, many tumors eventually become less ...

Early first cancer in BRCA1/2 ups risk in opposite breast

December 30, 2015
(HealthDay)—BRCA1/2 mutation carriers have increased risk of contralateral breast cancer (CBC), with age at first diagnosis a significant predictor of CBC risk, according to a study published online Dec. 23 in the Journal ...

New insights reported about the Angelina Jolie gene

March 4, 2016
Scientists from the Cancer Therapy & Research Center (CTRC) in San Antonio today (March 4) published work that provides deeper insight into how the Angelina Jolie gene, BRCA1, functions in normal breast tissue and how its ...

Researchers uncover novel role of BRCA1 in regulating the survival of skin stem cells

January 3, 2013
Our DNA, which stores our genetic information, is constantly exposed to damage. If not properly repaired, DNA damage can lead to cell death. This, in turn, can lead to tissue exhaustion and ageing, or induce mutations resulting ...

Recommended for you

Single-cell study in a childhood brain tumor affirms the importance of context

April 20, 2018
In defining the cellular context of diffuse midline gliomas, researchers find the cells fueling their growth and suggest a potential approach to treating them: forcing their cells to be more mature.

Aggressive breast cancer already has resistant tumour cells prior to chemotherapy

April 20, 2018
Difficult to treat and aggressive "triple-negative" breast cancer is chemoresistant even before chemotherapy begins, a new study by researchers from Karolinska Institutet and the University of Texas MD Anderson Cancer Center ...

Mechanism that drives development of liver cancer brought on by non-alcoholic fatty liver disease discovered

April 19, 2018
A team of researchers from several institutions in China has found a mechanism that appears to drive the development of a type of liver cancer not caused by alcohol consumption. In their paper published in the journal Science ...

Discovery adds to evidence that some children are predisposed to develop leukemia

April 19, 2018
St. Jude Children's Research Hospital researchers have made a discovery that expands the list of genes to include when screening individuals for possible increased susceptibility to childhood leukemia. The finding is reported ...

Chip-based blood test for multiple myeloma could make bone biopsies a relic of the past

April 19, 2018
The diagnosis and treatment of multiple myeloma, a cancer affecting plasma cells, traditionally forces patients to suffer through a painful bone biopsy. During that procedure, doctors insert a bone-biopsy needle through an ...

Scientists identify 170 potential lung cancer drug targets using unique cellular library

April 19, 2018
After testing more than 200,000 chemical compounds, UT Southwestern's Simmons Cancer Center researchers have identified 170 chemicals that are potential candidates for development into drug therapies for lung cancer.

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.