BRCA1 Mutational Complementation Induces Synthetic Viability

Nacson, Joseph; Marcantonio, Daniela Di; Wang, Yifan; Bernhardy, Andrea J.; Clausen, Emma; Xiang, Hua; Cai, Kathy Q.; Martı́nez, Esteban; Feng, Wei; Callén, Elsa; Wu, Wei; Gupta, Gaorav P.; Testa, Joseph R.; Nussenzweig, André; Sykes, Stephen M.; Johnson, Neil

doi:10.1016/j.molcel.2020.04.006

Cited by 41 publications

(128 citation statements)

References 36 publications

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“…5F-I). This nding imply that a unique role that DCs paly in bladder cancer microenvironment after cisplatin treatment 27 . However, the speci c function of cisplatin induced DCs in bladder cancer microenvironment needs to be further explored.…”

Section: Activation Of Cgas-sting Results In the Cd8 + T Cells And DCmentioning

confidence: 74%

Cisplatin Inhibits Bladder Cancer Proliferation Through cGAS-STING Pathway.

Chen

et al. 2020

Preprint

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Background Cisplatin is a commonly used adjuvant chemotherapy for advanced bladder cancer, but its immune related mechanism is still unclear. Exploration the immune effects of cisplatin in bladder cancer would complement the comprehensive mechanism of cisplatin and provide the basis for combination therapy of cisplatin and immunotherapy in bladder cancer. Methods We confirmed the immune effects of cisplatin on T24 and TCCSUP bladder cancer cell lines in vitro and exploration the important function of these immune effects in bladder cancer microenvironment in mice tumor model. Results We found cisplatin induced immune response in bladder cancer by RNA sequencing, and validated cGAS-STING signal was deeply involved in this response. Cisplatin induced cGAS-STING signal inhibited the proliferation of bladder cancer and increased the infiltration percentages of CD8 + T cells and dendritic cells in transplantation mice tumor model. Accumulation of dsDNA and the release of chromatin bound cGAS are important to activate downstream STING. Conclusion Our findings indicated a cisplatin related immune effects in bladder cancer, cisplatin combined with immunotherapy might have a synergistic effect for bladder cancer therapy.

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Section: Activation Of Cgas-sting Results In the Cd8 + T Cells And DCmentioning

confidence: 74%

Cisplatin Inhibits Bladder Cancer Proliferation Through cGAS-STING Pathway.

Chen

et al. 2020

Preprint

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“… MRE11 Initiate short-range resection Resect unprotected forks, promote fork restart [ 9 , 15 , 18 , 40 , 59 , 62 , 65 , 66 , 67 , 77 , 78 , 79 , 80 , 81 , 82 , 83 , 84 ]. PALB2 Promote BRCA2 recruitment via BRCA1 BRCA1-independent recruitment of BRCA2 [ 103 , 104 , 105 ]. PARP Break excision repair, Pol-theta mediated end joining Inhibit fork restoration, recruit MRE11, inhibits fork restoration, RAD51 stabilisation [ 53 , 86 , 141 , 163 ].…”

Section: Discussionmentioning

confidence: 99%

“…BRCA2 is largely recruited by BRCA1 through a bridging interaction with PALB2, required for HR (reviewed in [ 102 ]). However, the BRCA1-PALB2 interaction face is dispensable for replication fork protection [ 103 , 104 ]. Moreover in some lines of PARPi-resistant BRCA1-deficient cells, RAD51 foci formation is supported by PALB2-BRCA2 and ATR, illustrating an ATR-dependent, but BRCA1-independent mechanism for PALB2-BRCA2 recruitment [ 105 ].…”

Section: Degradation Of Reversed Forksmentioning

confidence: 99%

A fork in the road: Where homologous recombination and stalled replication fork protection part ways

Tye

Ronson

Morris

2021

Seminars in Cell & Developmental Biology

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In response to replication hindrances, DNA replication forks frequently stall and are remodelled into a four-way junction. In such a structure the annealed nascent strand is thought to resemble a DNA double-strand break and remodelled forks are vulnerable to nuclease attack by MRE11 and DNA2. Proteins that promote the recruitment, loading and stabilisation of RAD51 onto single-stranded DNA for homology search and strand exchange in homologous recombination (HR) repair and inter-strand cross-link repair also act to set up RAD51-mediated protection of nascent DNA at stalled replication forks. However, despite the similarities of these pathways, several lines of evidence indicate that fork protection is not simply analogous to the RAD51 loading step of HR. Protection of stalled forks not only requires separate functions of a number of recombination proteins, but also utilises nucleases important for the resection steps of HR in alternative ways. Here we discuss how fork protection arises and how its differences with HR give insights into the differing contexts of these two pathways.

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“…Mouse models of Brca2 partial loss of function also show increased tumorigenesis, with a particular predisposition to lymphomas [134,146]. Recently, two independent studies have developed Brca1 mouse models that disrupt the interaction between BRCA1 and PALB2 [141,142]. These mutations abrogate the RAD51-loading function of BRCA1 while maintaining intact BRCA1-dependent control of DSB resection.…”

Section: Genetic Interactions Between Hr Factors and Other Dna Damage Response And Repair Genesmentioning

confidence: 99%

Mouse Models for Deciphering the Impact of Homologous Recombination on Tumorigenesis

Matos-Rodrigues

Martini

2021

Cancers

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Homologous recombination (HR) is a fundamental evolutionarily conserved process that plays prime role(s) in genome stability maintenance through DNA repair and through the protection and resumption of arrested replication forks. Many HR genes are deregulated in cancer cells. Notably, the breast cancer genes BRCA1 and BRCA2, two important HR players, are the most frequently mutated genes in familial breast and ovarian cancer. Transgenic mice constitute powerful tools to unravel the intricate mechanisms controlling tumorigenesis in vivo. However, the genes central to HR are essential in mammals, and their knockout leads to early embryonic lethality in mice. Elaborated strategies have been developed to overcome this difficulty, enabling one to analyze the consequences of HR disruption in vivo. In this review, we first briefly present the molecular mechanisms of HR in mammalian cells to introduce each factor in the HR process. Then, we present the different mouse models of HR invalidation and the consequences of HR inactivation on tumorigenesis. Finally, we discuss the use of mouse models for the development of targeted cancer therapies as well as perspectives on the future potential for understanding the mechanisms of HR inactivation-driven tumorigenesis in vivo.

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BRCA1 Mutational Complementation Induces Synthetic Viability

Abstract: Highlights d A Brca1 coiled-coil (CC) mutation results in FA in mice d Brca1 exon 11 coding region is required for DNA end resection d Brca1 CC domain is essential for efficient RAD51 loading d Combining complementary mutant alleles partially restores HR

Cited by 41 publications

References 36 publications

Cisplatin Inhibits Bladder Cancer Proliferation Through cGAS-STING Pathway.

Cisplatin Inhibits Bladder Cancer Proliferation Through cGAS-STING Pathway.

A fork in the road: Where homologous recombination and stalled replication fork protection part ways

Mouse Models for Deciphering the Impact of Homologous Recombination on Tumorigenesis

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