Journal
CELLS
Volume 11, Issue 4, Pages -Publisher
MDPI
DOI: 10.3390/cells11040643
Keywords
CtIP; BARD1; BRCA1; synthetic lethality; replication stress; DNA damage
Categories
Funding
- Swiss National Science Foundation [31003A_156023, 31003A_176161]
- Swiss Cancer Research Foundation [KFS-3025-08-2012, KFS-3845-02-2016, KFS-470202-2019]
- Promedica Stiftung [1317/M]
- Stiftung zur Krebsbekampfung
- University Research Priority Program (URPP) Translational Cancer Research of the University of Zurich
- NF grants [PP00P3_179057, 310030_197003]
- European Research Council (ERC) under the European Union [ERC-2016-STG 714326]
- LENDULET-BIOMAG Grant [2018-342]
- European Regional Development Funds [GINOP-2.3.2-15-2016-00001]
- Vontobel-Stiftung
- Swiss National Science Foundation (SNF) [310030_197003, 31003A_156023] Funding Source: Swiss National Science Foundation (SNF)
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This research reveals the genetic interaction between CtIP and BARD1 plays a crucial role in maintaining genome integrity and cell survival, and may provide a potential therapeutic target for the treatment of BRCA-defective tumors.
Human CtIP is best known for its role in DNA end resection to initiate DNA double-strand break repair by homologous recombination. Recently, CtIP has also been shown to protect reversed replication forks from nucleolytic degradation upon DNA replication stress. However, still little is known about the DNA damage response (DDR) networks that preserve genome integrity and sustain cell survival in the context of CtIP insufficiency. Here, to reveal such potential buffering relationships, we screened a DDR siRNA library in CtIP-deficient cells to identify candidate genes that induce synthetic sickness/lethality (SSL). Our analyses unveil a negative genetic interaction between CtIP and BARD1, the heterodimeric binding partner of BRCA1. We found that simultaneous disruption of CtIP and BARD1 triggers enhanced apoptosis due to persistent replication stress-induced DNA lesions giving rise to chromosomal abnormalities. Moreover, we observed that the genetic interaction between CtIP and BARD1 occurs independently of the BRCA1-BARD1 complex formation and might be, therefore, therapeutical relevant for the treatment of BRCA-defective tumors.
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