Germline RBBP8 variants associated with early-onset breast cancer compromise replication fork stability

The COMPLEXO Network

doi:10.1172/JCI127521

Germline RBBP8 variants associated with early-onset breast cancer compromise replication fork stability

The COMPLEXO Network

Cancer and Genomic Sciences

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

4 Citations (Scopus)

260 Downloads (Pure)

Abstract

Haploinsufficiency of factors governing genome stability underlies hereditary breast and ovarian cancer. One significant pathway that is disabled as a result is homologous recombination repair (HRR). With the aim of identifying new candidate genes, we examined early-onset breast cancer patients negative for BRCA1 and BRCA2 pathogenic variants. Here, we focused on CtIP (RBBP8 gene), which mediates HRR through the end resection of DNA double-strand breaks (DSBs). Notably, these patients exhibited a number of rare germline RBBP8 variants. Functional analysis revealed that these variants did not affect DNA DSB end resection efficiency. However, expression of a subset of variants led to deleterious nucleolytic degradation of stalled DNA replication forks in a manner similar to that of cells lacking BRCA1 or BRCA2. In contrast to BRCA1 and BRCA2, CtIP deficiency promoted the helicase-driven destabilization of RAD51 nucleofilaments at damaged DNA replication forks. Taken together, our work identifies CtIP as a critical regulator of DNA replication fork integrity, which, when compromised, may predispose to the development of early-onset breast cancer.

Original language	English
Pages (from-to)	4069-4080
Number of pages	12
Journal	Journal of Clinical Investigation
Volume	130
Issue number	8
Early online date	7 May 2020
DOIs	https://doi.org/10.1172/JCI127521
Publication status	Published - 3 Aug 2020

ASJC Scopus subject areas

General Medicine

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This output contributes to the following UN Sustainable Development Goals (SDGs)

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ZarriziR2020Germline
https://doi.org/10.1172/JCI127521. Copyright © 2020, American Society for Clinical Investigation
Accepted author manuscript, 1.26 MBLicence: None: All rights reserved
ZarriziR2020GermlineVoR
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Final published version, 3.98 MBLicence: Other (please specify with Rights Statement)

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4 Citations
1 Article

Bod1l is required to suppress deleterious resection of stressed replication forks
Higgs, M., Reynolds, J., Winczura, A., Blackford, A., Borel, V., Miller, E., Zlatanou, A., Nieminuszczy, J., Ryan, E., Davies, N., Stankovic, T., Boulton, S., Niedzwiedz, W. & Stewart, G., 6 Aug 2015, In: Molecular Cell. 59, 3, p. 462-477
Research output: Contribution to journal › Article › peer-review

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88 Citations (Scopus)

336 Downloads (Pure)

1 Finished

The impact of non-histone protein methylation by set1a in maintaining genome stability and preventing disease
Higgs, M. (Principal Investigator)
Medical Research Council
1/04/17 → 31/03/23
Project: Research Councils

Cite this

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title = "Germline RBBP8 variants associated with early-onset breast cancer compromise replication fork stability",

abstract = "Haploinsufficiency of factors governing genome stability underlies hereditary breast and ovarian cancer. One significant pathway that is disabled as a result is homologous recombination repair (HRR). With the aim of identifying new candidate genes, we examined early-onset breast cancer patients negative for BRCA1 and BRCA2 pathogenic variants. Here, we focused on CtIP (RBBP8 gene), which mediates HRR through the end resection of DNA double-strand breaks (DSBs). Notably, these patients exhibited a number of rare germline RBBP8 variants. Functional analysis revealed that these variants did not affect DNA DSB end resection efficiency. However, expression of a subset of variants led to deleterious nucleolytic degradation of stalled DNA replication forks in a manner similar to that of cells lacking BRCA1 or BRCA2. In contrast to BRCA1 and BRCA2, CtIP deficiency promoted the helicase-driven destabilization of RAD51 nucleofilaments at damaged DNA replication forks. Taken together, our work identifies CtIP as a critical regulator of DNA replication fork integrity, which, when compromised, may predispose to the development of early-onset breast cancer.",

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AU - Bose, Muthiah

AU - Kousholt, Arne Nedergaard

AU - Rösner, Heike

AU - Ejlertsen, Bent

AU - Stewart, Grant

AU - Nielsen, Finn Cilius

AU - Sørensen, Claus

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AB - Haploinsufficiency of factors governing genome stability underlies hereditary breast and ovarian cancer. One significant pathway that is disabled as a result is homologous recombination repair (HRR). With the aim of identifying new candidate genes, we examined early-onset breast cancer patients negative for BRCA1 and BRCA2 pathogenic variants. Here, we focused on CtIP (RBBP8 gene), which mediates HRR through the end resection of DNA double-strand breaks (DSBs). Notably, these patients exhibited a number of rare germline RBBP8 variants. Functional analysis revealed that these variants did not affect DNA DSB end resection efficiency. However, expression of a subset of variants led to deleterious nucleolytic degradation of stalled DNA replication forks in a manner similar to that of cells lacking BRCA1 or BRCA2. In contrast to BRCA1 and BRCA2, CtIP deficiency promoted the helicase-driven destabilization of RAD51 nucleofilaments at damaged DNA replication forks. Taken together, our work identifies CtIP as a critical regulator of DNA replication fork integrity, which, when compromised, may predispose to the development of early-onset breast cancer.

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Germline RBBP8 variants associated with early-onset breast cancer compromise replication fork stability

Abstract

ASJC Scopus subject areas

UN SDGs

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Research output

Bod1l is required to suppress deleterious resection of stressed replication forks

Projects

The impact of non-histone protein methylation by set1a in maintaining genome stability and preventing disease

Cite this