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The antitumorigenic roles of BRCA1–BARD1 in DNA repair and replication

Nature Reviews Molecular Cell Biology volume 21, pages 284–299 (2020)Cite this article

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Abstract

The tumour suppressor breast cancer type 1 susceptibility protein (BRCA1) promotes DNA double-strand break (DSB) repair by homologous recombination and protects DNA replication forks from attrition. BRCA1 partners with BRCA1-associated RING domain protein 1 (BARD1) and other tumour suppressor proteins to mediate the initial nucleolytic resection of DNA lesions and the recruitment and regulation of the recombinase RAD51. The discovery of the opposing functions of BRCA1 and the p53-binding protein 1 (53BP1)-associated complex in DNA resection sheds light on how BRCA1 influences the choice of homologous recombination over non-homologous end joining and potentially other mutagenic pathways of DSB repair. Understanding the functional crosstalk between BRCA1–BARD1 and its cofactors and antagonists will illuminate the molecular basis of cancers that arise from a deficiency or misregulation of chromosome damage repair and replication fork maintenance. Such knowledge will also be valuable for understanding acquired tumour resistance to poly(ADP-ribose) polymerase (PARP) inhibitors and other therapeutics and for the development of new treatments. In this Review, we discuss recent advances in elucidating the mechanisms by which BRCA1–BARD1 functions in DNA repair, replication fork maintenance and tumour suppression, and its therapeutic relevance.

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Fig. 1: The functional domains of BRCA1 and BARD1.
Fig. 2: The roles of BRCA1–BARD1 in DSB repair by homologous recombination.
Fig. 3: Antagonistic roles of BRCA1–BARD1 and the 53BP1 complex.
Fig. 4: Roles of the BRCA1 complex in protecting regressed replication forks and resolving R-loops.

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Acknowledgements

The studies in the laboratories of the authors were supported by Cancer Research UK, the UK Medical Research Council, the University of Oxford and the European Union’s Horizon 2020 research and innovation program under the Marie Skłodowska-Curie grant agreement No. 722729 (M.T.), and by Cancer Prevention and Research Institute of Texas (CPRIT) REI award RR180029, a Grey Foundation Team Science award and US National Institutes of Health research grant awards R35 CA241801, RO1 CA168635 and RO1 ES007061 (to P.S.). P.S. is a CPRIT Scholar of Cancer Research and the Robert A. Welch Distinguished Chair in Chemistry (AQ-0012). The authors are grateful to Y. Kwon for help with artwork and to W. Zhao and J. Daley for providing valuable feedback on the manuscript.

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  1. Genome Stability and Tumourigenesis Group, Oxford Institute for Radiation Oncology, Department of Oncology, University of Oxford, Oxford, UK

    Madalena Tarsounas

  2. Department of Biochemistry and Structural Biology, University of Texas Health Science Center, San Antonio, TX, USA

    Patrick Sung

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Glossary

R-loops

Three-stranded nucleic acid structures that arise during transcription, consisting of an RNA–DNA hybrid formed by annealing of the nascent transcript with its DNA template. The non-template DNA is displaced as single-stranded DNA.

Synthetic lethality

Induction of cell death (lethality) by simultaneously inactivating two different biological pathways or genes, which normally do not affect cell viability inactivated individually.

Ionizing radiation-induced nuclear foci

Subnuclear domains into which factors needed for DNA damage signalling and repair concentrate on exposure to ionizing radiation. Their formation and resolution reflect the robustness of the cellular response to ionizing radiation.

G-quadruplexes

Non-canonical DNA (or RNA) structures consisting of stacks of two or more guanine quartets, each stabilized by a monovalent cation. G-quadruplexes form spontaneously on guanine-rich single-stranded DNA during DNA replication and transcription.

Radial chromosomes

Fused chromosomes that arise from aberrant repair of DNA double-strand breaks or stalled replication forks, or from incomplete resolution of repair intermediates.

Fanconi anaemia

A multigenic disorder characterized by bone marrow failure and cancer predisposition, owing to an inability to properly process DNA interstrand crosslinks and other DNA lesions.

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Tarsounas, M., Sung, P. The antitumorigenic roles of BRCA1–BARD1 in DNA repair and replication. Nat Rev Mol Cell Biol 21, 284–299 (2020). https://doi.org/10.1038/s41580-020-0218-z

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