DNA binding and RAD51 engagement by the BRCA2 C-terminus orchestrate DNA repair and replication fork preservation

Youngho Kwon; Heike Rösner; Weixing Zhao; Platon Selemenakis; Zhuoling He; Ajinkya S. Kawale; Jeffrey N. Katz; Cody M. Rogers; Francisco E. Neal; Aida Badamchi Shabestari; Valdemaras Petrosius; Akhilesh K. Singh; Marina Z. Joel; Lucy Lu; Stephen P. Holloway; Sandeep Burma; Bipasha Mukherjee; Robert Hromas; Alexander Mazin; Claudia Wiese; Claus S. Sørensen; Patrick Sung

doi:10.1038/s41467-023-36211-x

DNA binding and RAD51 engagement by the BRCA2 C-terminus orchestrate DNA repair and replication fork preservation

Youngho Kwon, Heike Rösner, Weixing Zhao, Platon Selemenakis, Zhuoling He, Ajinkya S. Kawale, Jeffrey N. Katz, Cody M. Rogers, Francisco E. Neal, Aida Badamchi Shabestari, Valdemaras Petrosius, Akhilesh K. Singh, Marina Z. Joel, Lucy Lu, Stephen P. Holloway, Sandeep Burma, Bipasha Mukherjee, Robert Hromas, Alexander Mazin, Claudia WieseClaus S. Sørensen, Patrick Sung

Research output: Contribution to journal › Article › peer-review

17 Scopus citations

Abstract

The tumor suppressor BRCA2 participates in DNA double-strand break repair by RAD51-dependent homologous recombination and protects stressed DNA replication forks from nucleolytic attack. We demonstrate that the C-terminal Recombinase Binding (CTRB) region of BRCA2, encoded by gene exon 27, harbors a DNA binding activity. CTRB alone stimulates the DNA strand exchange activity of RAD51 and permits the utilization of RPA-coated ssDNA by RAD51 for strand exchange. Moreover, CTRB functionally synergizes with the Oligonucleotide Binding fold containing DNA binding domain and BRC4 repeat of BRCA2 in RPA-RAD51 exchange on ssDNA. Importantly, we show that the DNA binding and RAD51 interaction attributes of the CTRB are crucial for homologous recombination and protection of replication forks against MRE11-mediated attrition. Our findings shed light on the role of the CTRB region in genome repair, reveal remarkable functional plasticity of BRCA2, and help explain why deletion of Brca2 exon 27 impacts upon embryonic lethality.

Original language	English (US)
Article number	432
Journal	Nature communications
Volume	14
Issue number	1
DOIs	https://doi.org/10.1038/s41467-023-36211-x
State	Published - Dec 2023

ASJC Scopus subject areas

General Chemistry
General Biochemistry, Genetics and Molecular Biology
General Physics and Astronomy

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Kwon, Y., Rösner, H., Zhao, W., Selemenakis, P., He, Z., Kawale, A. S., Katz, J. N., Rogers, C. M., Neal, F. E., Badamchi Shabestari, A., Petrosius, V., Singh, A. K., Joel, M. Z., Lu, L., Holloway, S. P., Burma, S., Mukherjee, B., Hromas, R., Mazin, A., ... Sung, P. (2023). DNA binding and RAD51 engagement by the BRCA2 C-terminus orchestrate DNA repair and replication fork preservation. Nature communications, 14(1), Article 432. https://doi.org/10.1038/s41467-023-36211-x

Kwon, Y, Rösner, H, Zhao, W, Selemenakis, P, He, Z, Kawale, AS, Katz, JN, Rogers, CM, Neal, FE, Badamchi Shabestari, A, Petrosius, V, Singh, AK, Joel, MZ, Lu, L, Holloway, SP, Burma, S , Mukherjee, B , Hromas, R , Mazin, A, Wiese, C, Sørensen, CS & Sung, P 2023, 'DNA binding and RAD51 engagement by the BRCA2 C-terminus orchestrate DNA repair and replication fork preservation', Nature communications, vol. 14, no. 1, 432. https://doi.org/10.1038/s41467-023-36211-x

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title = "DNA binding and RAD51 engagement by the BRCA2 C-terminus orchestrate DNA repair and replication fork preservation",

abstract = "The tumor suppressor BRCA2 participates in DNA double-strand break repair by RAD51-dependent homologous recombination and protects stressed DNA replication forks from nucleolytic attack. We demonstrate that the C-terminal Recombinase Binding (CTRB) region of BRCA2, encoded by gene exon 27, harbors a DNA binding activity. CTRB alone stimulates the DNA strand exchange activity of RAD51 and permits the utilization of RPA-coated ssDNA by RAD51 for strand exchange. Moreover, CTRB functionally synergizes with the Oligonucleotide Binding fold containing DNA binding domain and BRC4 repeat of BRCA2 in RPA-RAD51 exchange on ssDNA. Importantly, we show that the DNA binding and RAD51 interaction attributes of the CTRB are crucial for homologous recombination and protection of replication forks against MRE11-mediated attrition. Our findings shed light on the role of the CTRB region in genome repair, reveal remarkable functional plasticity of BRCA2, and help explain why deletion of Brca2 exon 27 impacts upon embryonic lethality.",

author = "Youngho Kwon and Heike R{\"o}sner and Weixing Zhao and Platon Selemenakis and Zhuoling He and Kawale, {Ajinkya S.} and Katz, {Jeffrey N.} and Rogers, {Cody M.} and Neal, {Francisco E.} and {Badamchi Shabestari}, Aida and Valdemaras Petrosius and Singh, {Akhilesh K.} and Joel, {Marina Z.} and Lucy Lu and Holloway, {Stephen P.} and Sandeep Burma and Bipasha Mukherjee and Robert Hromas and Alexander Mazin and Claudia Wiese and S{\o}rensen, {Claus S.} and Patrick Sung",

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doi = "10.1038/s41467-023-36211-x",

language = "English (US)",

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AU - Kwon, Youngho

AU - Rösner, Heike

AU - Zhao, Weixing

AU - Selemenakis, Platon

AU - He, Zhuoling

AU - Kawale, Ajinkya S.

AU - Katz, Jeffrey N.

AU - Rogers, Cody M.

AU - Neal, Francisco E.

AU - Badamchi Shabestari, Aida

AU - Petrosius, Valdemaras

AU - Singh, Akhilesh K.

AU - Joel, Marina Z.

AU - Lu, Lucy

AU - Holloway, Stephen P.

AU - Burma, Sandeep

AU - Mukherjee, Bipasha

AU - Hromas, Robert

AU - Mazin, Alexander

AU - Wiese, Claudia

AU - Sørensen, Claus S.

AU - Sung, Patrick

PY - 2023/12

Y1 - 2023/12

N2 - The tumor suppressor BRCA2 participates in DNA double-strand break repair by RAD51-dependent homologous recombination and protects stressed DNA replication forks from nucleolytic attack. We demonstrate that the C-terminal Recombinase Binding (CTRB) region of BRCA2, encoded by gene exon 27, harbors a DNA binding activity. CTRB alone stimulates the DNA strand exchange activity of RAD51 and permits the utilization of RPA-coated ssDNA by RAD51 for strand exchange. Moreover, CTRB functionally synergizes with the Oligonucleotide Binding fold containing DNA binding domain and BRC4 repeat of BRCA2 in RPA-RAD51 exchange on ssDNA. Importantly, we show that the DNA binding and RAD51 interaction attributes of the CTRB are crucial for homologous recombination and protection of replication forks against MRE11-mediated attrition. Our findings shed light on the role of the CTRB region in genome repair, reveal remarkable functional plasticity of BRCA2, and help explain why deletion of Brca2 exon 27 impacts upon embryonic lethality.

AB - The tumor suppressor BRCA2 participates in DNA double-strand break repair by RAD51-dependent homologous recombination and protects stressed DNA replication forks from nucleolytic attack. We demonstrate that the C-terminal Recombinase Binding (CTRB) region of BRCA2, encoded by gene exon 27, harbors a DNA binding activity. CTRB alone stimulates the DNA strand exchange activity of RAD51 and permits the utilization of RPA-coated ssDNA by RAD51 for strand exchange. Moreover, CTRB functionally synergizes with the Oligonucleotide Binding fold containing DNA binding domain and BRC4 repeat of BRCA2 in RPA-RAD51 exchange on ssDNA. Importantly, we show that the DNA binding and RAD51 interaction attributes of the CTRB are crucial for homologous recombination and protection of replication forks against MRE11-mediated attrition. Our findings shed light on the role of the CTRB region in genome repair, reveal remarkable functional plasticity of BRCA2, and help explain why deletion of Brca2 exon 27 impacts upon embryonic lethality.

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DNA binding and RAD51 engagement by the BRCA2 C-terminus orchestrate DNA repair and replication fork preservation

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