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

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Standard

Germline RBBP8 variants associated with early-onset breast cancer compromise replication fork stability. / Zarrizi, Reihaneh; Higgs, Martin R; Voßgröne, Karolin; Rossing, Maria; Bertelsen, Birgitte; Bose, Muthiah; Kousholt, Arne Nedergaard; Rösner, Heike; Network, The Complexo; Ejlertsen, Bent; Stewart, Grant S; Nielsen, Finn Cilius; Sørensen, Claus S.

I: The Journal of Clinical Investigation, Bind 130, Nr. 8, 03.08.2020, s. 4069-4080.

Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt

Harvard

Zarrizi, R, Higgs, MR, Voßgröne, K, Rossing, M, Bertelsen, B, Bose, M, Kousholt, AN, Rösner, H, Network, TC, Ejlertsen, B, Stewart, GS, Nielsen, FC & Sørensen, CS 2020, 'Germline RBBP8 variants associated with early-onset breast cancer compromise replication fork stability', The Journal of Clinical Investigation, bind 130, nr. 8, s. 4069-4080. https://doi.org/10.1172/JCI127521

APA

Zarrizi, R., Higgs, M. R., Voßgröne, K., Rossing, M., Bertelsen, B., Bose, M., Kousholt, A. N., Rösner, H., Network, T. C., Ejlertsen, B., Stewart, G. S., Nielsen, F. C., & Sørensen, C. S. (2020). Germline RBBP8 variants associated with early-onset breast cancer compromise replication fork stability. The Journal of Clinical Investigation, 130(8), 4069-4080. https://doi.org/10.1172/JCI127521

Vancouver

Zarrizi R, Higgs MR, Voßgröne K, Rossing M, Bertelsen B, Bose M o.a. Germline RBBP8 variants associated with early-onset breast cancer compromise replication fork stability. The Journal of Clinical Investigation. 2020 aug. 3;130(8):4069-4080. https://doi.org/10.1172/JCI127521

Author

Zarrizi, Reihaneh ; Higgs, Martin R ; Voßgröne, Karolin ; Rossing, Maria ; Bertelsen, Birgitte ; Bose, Muthiah ; Kousholt, Arne Nedergaard ; Rösner, Heike ; Network, The Complexo ; Ejlertsen, Bent ; Stewart, Grant S ; Nielsen, Finn Cilius ; Sørensen, Claus S. / Germline RBBP8 variants associated with early-onset breast cancer compromise replication fork stability. I: The Journal of Clinical Investigation. 2020 ; Bind 130, Nr. 8. s. 4069-4080.

Bibtex

@article{e803edc996314eafb3e0040ace25aaed,
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 = "Reihaneh Zarrizi and Higgs, {Martin R} 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 Network, {The Complexo} and Bent Ejlertsen and Stewart, {Grant S} and Nielsen, {Finn Cilius} and S{\o}rensen, {Claus S}",
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 - Zarrizi, Reihaneh

AU - Higgs, Martin R

AU - Voßgröne, Karolin

AU - Rossing, Maria

AU - Bertelsen, Birgitte

AU - Bose, Muthiah

AU - Kousholt, Arne Nedergaard

AU - Rösner, Heike

AU - Network, The Complexo

AU - Ejlertsen, Bent

AU - Stewart, Grant S

AU - Nielsen, Finn Cilius

AU - Sørensen, Claus S

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.

U2 - 10.1172/JCI127521

DO - 10.1172/JCI127521

M3 - Journal 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 -

ID: 251833598