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Updated: Apr 24, 2026
Characterizing DNA Repair Processes at Transient and Long-lasting Double-strand DNA Breaks by Immunofluorescence Microscopy
Published on: June 8, 2018
Systematic screening reveals a role for BRCA1 in the response to transcription-associated DNA damage
Sarah J Hill1, Thomas Rolland2, Guillaume Adelmant3
1Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA; Department of Genetics, Harvard Medical School, Boston, Massachusetts 02115, USA;
Abstract:
BRCA1 is a breast and ovarian tumor suppressor. Given its numerous incompletely understood functions and the possibility that more exist, we performed complementary systematic screens in search of new BRCA1 protein-interacting partners. New BRCA1 functions and/or a better understanding of existing ones were sought. Among the new interacting proteins identified, genetic interactions were detected between BRCA1 and four of the interactors: TONSL, SETX, TCEANC, and TCEA2. Genetic interactions were also detected between BRCA1 and certain interactors of TONSL, including both members of the FACT complex. From these results, a new BRCA1 function in the response to transcription-associated DNA damage was detected. Specifically, new roles for BRCA1 in the restart of transcription after UV damage and in preventing or repairing damage caused by stabilized R loops were identified. These roles are likely carried out together with some of the newly identified interactors. This new function may be important in BRCA1 tumor suppression, since the expression of several interactors, including some of the above-noted transcription proteins, is repeatedly aberrant in both breast and ovarian cancers.
Insights
Researchers discovered new BRCA1 protein interactions, revealing its role in DNA damage response during transcription. This finding sheds light on BRCA1
Area of Science:
- Molecular Biology
- Genetics
- Cancer Research
Background:
- BRCA1 is a critical tumor suppressor gene involved in breast and ovarian cancer.
- The full spectrum of BRCA1 functions remains incompletely understood.
- Identifying novel protein interactions can elucidate new cellular roles for BRCA1.
Purpose of the Study:
- To identify new BRCA1 protein-interacting partners through systematic screening.
- To investigate potential new functions of BRCA1, particularly in DNA damage response.
- To explore the relevance of these interactions and functions in the context of cancer.
Main Methods:
- Systematic screens were employed to identify BRCA1 protein-interacting partners.
- Genetic interaction analyses were performed between BRCA1 and identified interactors.
- The study examined BRCA1's role in transcription-associated DNA damage, including UV damage and R-loop stabilization.
Main Results:
- New BRCA1 protein interactors were identified, including TONSL, SETX, TCEANC, and TCEA2.
- Genetic interactions were confirmed between BRCA1 and several of these interactors, as well as TONSL interactors like the FACT complex.
- A novel function for BRCA1 in responding to transcription-associated DNA damage was uncovered, specifically in transcription restart post-UV damage and in managing R-loop-induced DNA damage.
Conclusions:
- BRCA1 plays a previously unrecognized role in the cellular response to transcription-associated DNA damage.
- This new function involves transcription restart and the prevention or repair of R-loop-associated DNA damage, likely mediated by newly identified interactors.
- Aberrant expression of these interactors in breast and ovarian cancers suggests this newly identified BRCA1 function is significant for its tumor suppressor activity.
