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

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Germline RBBP8 variants associated with early-onset breast cancer compromise replication fork stability. / The COMPLEXO Network.

In: Journal of Clinical Investigation, Vol. 130, No. 8, 03.08.2020, p. 4069-4080.

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@article{70a69710ac69477eb51d8d6a62c8e277,
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.",
author = "{The COMPLEXO Network} and Reihaneh Zarrizi and Martin Higgs and Karolin Vo{\ss}gr{\"o}ne and Maria Rossing and Birgitte Bertelsen and Muthiah Bose and Kousholt, {Arne Nedergaard} and Heike R{\"o}sner and Bent Ejlertsen and Grant Stewart and Nielsen, {Finn Cilius} and Claus S{\o}rensen",
year = "2020",
month = aug,
day = "3",
doi = "10.1172/JCI127521",
language = "English",
volume = "130",
pages = "4069--4080",
journal = "Journal of Clinical Investigation",
issn = "0021-9738",
publisher = "American Society for Clinical Investigation",
number = "8",

}

RIS

TY - JOUR

T1 - Germline RBBP8 variants associated with early-onset breast cancer compromise replication fork stability

AU - The COMPLEXO Network

AU - Zarrizi, Reihaneh

AU - Higgs, Martin

AU - Voßgröne, Karolin

AU - Rossing, Maria

AU - Bertelsen, Birgitte

AU - Bose, Muthiah

AU - Kousholt, Arne Nedergaard

AU - Rösner, Heike

AU - Ejlertsen, Bent

AU - Stewart, Grant

AU - Nielsen, Finn Cilius

AU - Sørensen, Claus

PY - 2020/8/3

Y1 - 2020/8/3

N2 - 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.

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.

UR - http://www.scopus.com/inward/record.url?scp=85089059741&partnerID=8YFLogxK

U2 - 10.1172/JCI127521

DO - 10.1172/JCI127521

M3 - Article

C2 - 32379725

VL - 130

SP - 4069

EP - 4080

JO - Journal of Clinical Investigation

JF - Journal of Clinical Investigation

SN - 0021-9738

IS - 8

ER -