Promotion of BRCA2-Dependent Homologous Recombination by DSS1 via RPA Targeting and DNA Mimicry

Weixing Zhao; Sivaraja Vaithiyalingam; Joseph San Filippo; David G. Maranon; Judit Jimenez-Sainz; Gerald V. Fontenay; Youngho Kwon; Stanley G. Leung; Lucy Lu; Ryan B. Jensen; Walter J. Chazin; Claudia Wiese; Patrick Sung

doi:10.1016/j.molcel.2015.05.032

Promotion of BRCA2-Dependent Homologous Recombination by DSS1 via RPA Targeting and DNA Mimicry

Weixing Zhao, Sivaraja Vaithiyalingam, Joseph San Filippo, David G. Maranon, Judit Jimenez-Sainz, Gerald V. Fontenay, Youngho Kwon, Stanley G. Leung, Lucy Lu, Ryan B. Jensen, Walter J. Chazin, Claudia Wiese, Patrick Sung

Biochemistry & Structural Biology

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

66 Scopus citations

Abstract

The tumor suppressor BRCA2 is thought to facilitate the handoff of ssDNA from replication protein A (RPA) to the RAD51 recombinase during DNA break and replication fork repair by homologous recombination. However, we find that RPA-RAD51 exchange requires the BRCA2 partner DSS1. Biochemical, structural, and invivo analyses reveal that DSS1 allows the BRCA2-DSS1 complex to physically andfunctionally interact with RPA. Mechanistically, DSS1 acts as a DNA mimic to attenuate the affinity of RPA for ssDNA. A mutation in the solvent-exposed acidic domain of DSS1 compromises the efficacy of RPA-RAD51 exchange. Thus, by targeting RPA and mimicking DNA, DSS1 functions with BRCA2 in a two-component homologous recombination mediator complex in genome maintenance and tumor suppression. Our findings may provide a paradigm for understanding the roles of DSS1 in other biological processes.

Original language	English (US)
Pages (from-to)	176-187
Number of pages	12
Journal	Molecular Cell
Volume	59
Issue number	2
DOIs	https://doi.org/10.1016/j.molcel.2015.05.032
State	Published - Jul 16 2015

ASJC Scopus subject areas

Molecular Biology
Cell Biology

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Promotion of BRCA2-Dependent Homologous Recombination by DSS1 via RPA Targeting and DNA Mimicry. / Zhao, Weixing; Vaithiyalingam, Sivaraja; San Filippo, Joseph; Maranon, David G.; Jimenez-Sainz, Judit; Fontenay, Gerald V.; Kwon, Youngho; Leung, Stanley G.; Lu, Lucy; Jensen, Ryan B.; Chazin, Walter J.; Wiese, Claudia; Sung, Patrick.

In: Molecular Cell, Vol. 59, No. 2, 16.07.2015, p. 176-187.

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

Zhao, Weixing ; Vaithiyalingam, Sivaraja ; San Filippo, Joseph ; Maranon, David G. ; Jimenez-Sainz, Judit ; Fontenay, Gerald V. ; Kwon, Youngho ; Leung, Stanley G. ; Lu, Lucy ; Jensen, Ryan B. ; Chazin, Walter J. ; Wiese, Claudia ; Sung, Patrick. / Promotion of BRCA2-Dependent Homologous Recombination by DSS1 via RPA Targeting and DNA Mimicry. In: Molecular Cell. 2015 ; Vol. 59, No. 2. pp. 176-187.

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title = "Promotion of BRCA2-Dependent Homologous Recombination by DSS1 via RPA Targeting and DNA Mimicry",

abstract = "The tumor suppressor BRCA2 is thought to facilitate the handoff of ssDNA from replication protein A (RPA) to the RAD51 recombinase during DNA break and replication fork repair by homologous recombination. However, we find that RPA-RAD51 exchange requires the BRCA2 partner DSS1. Biochemical, structural, and invivo analyses reveal that DSS1 allows the BRCA2-DSS1 complex to physically andfunctionally interact with RPA. Mechanistically, DSS1 acts as a DNA mimic to attenuate the affinity of RPA for ssDNA. A mutation in the solvent-exposed acidic domain of DSS1 compromises the efficacy of RPA-RAD51 exchange. Thus, by targeting RPA and mimicking DNA, DSS1 functions with BRCA2 in a two-component homologous recombination mediator complex in genome maintenance and tumor suppression. Our findings may provide a paradigm for understanding the roles of DSS1 in other biological processes.",

author = "Weixing Zhao and Sivaraja Vaithiyalingam and {San Filippo}, Joseph and Maranon, {David G.} and Judit Jimenez-Sainz and Fontenay, {Gerald V.} and Youngho Kwon and Leung, {Stanley G.} and Lucy Lu and Jensen, {Ryan B.} and Chazin, {Walter J.} and Claudia Wiese and Patrick Sung",

note = "Funding Information: We thank Stephen Kowalczykowski for the phCMV1-BRCA2 vector and Alan Ashworth for the pEGFP-DSS1 vector. This work was supported by US National Institutes of Health grants ES015252, ES007061, CA168635, CA92584, ES021454, and GM65484. Access to facilities was supported by P30 ES00267 and P30 CA068485. NMR instrumentation was supported by grants from the NSF (0922862), NIH (S10 RR025677), and Vanderbilt University matching funds. ",

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N1 - Funding Information: We thank Stephen Kowalczykowski for the phCMV1-BRCA2 vector and Alan Ashworth for the pEGFP-DSS1 vector. This work was supported by US National Institutes of Health grants ES015252, ES007061, CA168635, CA92584, ES021454, and GM65484. Access to facilities was supported by P30 ES00267 and P30 CA068485. NMR instrumentation was supported by grants from the NSF (0922862), NIH (S10 RR025677), and Vanderbilt University matching funds.

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N2 - The tumor suppressor BRCA2 is thought to facilitate the handoff of ssDNA from replication protein A (RPA) to the RAD51 recombinase during DNA break and replication fork repair by homologous recombination. However, we find that RPA-RAD51 exchange requires the BRCA2 partner DSS1. Biochemical, structural, and invivo analyses reveal that DSS1 allows the BRCA2-DSS1 complex to physically andfunctionally interact with RPA. Mechanistically, DSS1 acts as a DNA mimic to attenuate the affinity of RPA for ssDNA. A mutation in the solvent-exposed acidic domain of DSS1 compromises the efficacy of RPA-RAD51 exchange. Thus, by targeting RPA and mimicking DNA, DSS1 functions with BRCA2 in a two-component homologous recombination mediator complex in genome maintenance and tumor suppression. Our findings may provide a paradigm for understanding the roles of DSS1 in other biological processes.

AB - The tumor suppressor BRCA2 is thought to facilitate the handoff of ssDNA from replication protein A (RPA) to the RAD51 recombinase during DNA break and replication fork repair by homologous recombination. However, we find that RPA-RAD51 exchange requires the BRCA2 partner DSS1. Biochemical, structural, and invivo analyses reveal that DSS1 allows the BRCA2-DSS1 complex to physically andfunctionally interact with RPA. Mechanistically, DSS1 acts as a DNA mimic to attenuate the affinity of RPA for ssDNA. A mutation in the solvent-exposed acidic domain of DSS1 compromises the efficacy of RPA-RAD51 exchange. Thus, by targeting RPA and mimicking DNA, DSS1 functions with BRCA2 in a two-component homologous recombination mediator complex in genome maintenance and tumor suppression. Our findings may provide a paradigm for understanding the roles of DSS1 in other biological processes.

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