Fork Protection and Therapy Resistance in Hereditary Breast Cancer

Cantor, Sharon B.; Calvo, Jennifer A.

doi:10.1101/sqb.2017.82.034413

Cited by 19 publications

(12 citation statements)

References 99 publications

(162 reference statements)

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“…In BRCA1- and BRCA2-deficient cells, MRE11-dependent nucleolytic processing of reversed forks leads to fork degradation ( Schlacher et al, 2011 ; Schlacher et al, 2012 ). Preventing fork reversal through depletion of fork remodelers such as SMARCAL1, ZRANB3, or helicase-like transcription factor (HLTF) restores fork protection to BRCA1 and BRCA2-deficient cells and in some cases improves resistance to stress-inducing agents ( Kolinjivadi et al, 2017 ; Taglialatela et al, 2017 ; Cantor and Calvo, 2017 ; Mijic et al, 2017 ).…”

Section: Introductionmentioning

confidence: 99%

Opposing Roles of FANCJ and HLTF Protect Forks and Restrain Replication during Stress

et al. 2018

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SUMMARY The DNA helicase FANCJ is mutated in hereditary breast and ovarian cancer and Fanconi anemia (FA). Nevertheless, how loss of FANCJ translates to disease pathogenesis remains unclear. We addressed this question by analyzing proteins associated with replication forks in cells with or without FANCJ. We demonstrate that FANCJ-knockout (FANCJ-KO) cells have alterations in the replisome that are consistent with enhanced replication stress, including an aberrant accumulation of the fork remodeling factor helicase-like transcription factor (HLTF). Correspondingly, HLTF contributes to fork degradation in FANCJ-KO cells. Unexpectedly, the unrestrained DNA synthesis that characterizes HLTF-deficient cells is FANCJ dependent and correlates with S1 nuclease sensitivity and fork degradation. These results suggest that FANCJ and HLTF promote replication fork integrity, in part by counteracting each other to keep fork remodeling and elongation in check. Indicating one protein compensates for loss of the other, loss of both HLTF and FANCJ causes a more severe replication stress response.

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Section: Introductionmentioning

confidence: 99%

Opposing Roles of FANCJ and HLTF Protect Forks and Restrain Replication during Stress

et al. 2018

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“…Notably, DNA crosslinks do not appear to initially cause replication forks to collapse and can be bypassed (8,9). Moreover, in the majority of genetic models currently reported, restored FP fails to restore cisplatin resistance, suggesting the cisplatin lesions do not collapse forks, and therefore calls into question how cisplatin crosslinks could be converted into DSBs (4,10). Most saliently, indicating that the fundamental sensitizing lesion may in fact not be a DSB, reports indicate even HR proficient cells can nevertheless display hypersensitivity to cisplatin and other genotoxic agents (11)(12)(13).…”

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Replication Gaps Underlie BRCA Deficiency and Therapy Response

et al. 2021

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Defects in DNA repair and the protection of stalled DNA replication forks are thought to underlie the chemosensitivity of tumors deficient in the hereditary breast cancer genes BRCA1 and BRCA2 (BRCA). Challenging this assumption are recent findings that indicate chemotherapies, such as cisplatin used to treat BRCA-deficient tumors, do not initially cause DNA double-strand breaks (DSB). Here, we show that ssDNA replication gaps underlie the hypersensitivity of BRCA-deficient cancer and that defects in homologous recombination (HR) or fork protection (FP) do not. In BRCA-deficient cells, ssDNA gaps developed because replication was not effectively restrained in response to stress. Gap suppression by either restoration of fork restraint or gap filling conferred therapy resistance in tissue culture and BRCA patient tumors. In contrast, restored FP and HR could be uncoupled from therapy resistance when gaps were present. Moreover, DSBs were not detected after therapy when apoptosis was inhibited, supporting a framework in which DSBs are not directly induced by genotoxic agents, but rather are induced from cell death nucleases and are not fundamental to the mechanism of action of genotoxic agents. Together, these data indicate that ssDNA replication gaps underlie the BRCA cancer phenotype, “BRCAness,” and we propose they are fundamental to the mechanism of action of genotoxic chemotherapies. Significance: This study suggests that ssDNA replication gaps are fundamental to the toxicity of genotoxic agents and underlie the BRCA-cancer phenotype “BRCAness,” yielding promising biomarkers, targets, and opportunities to resensitize refractory disease. See related commentary by Canman, p. 1214

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“…Moreover, recent findings indicate that cisplatin toxicity in triple negative breast cancer is unrelated to loss of DNA repair factors (Heijink et al, 2019). In addition, in several distinct models restored FP fails to restore cisplatin resistance, suggesting FP is uncoupled from the mechanism of resistance (Feng and Jasin, 2017) (Cantor and Calvo, 2018). Most saliently, indicating that the underlying sensitizing lesion may in fact not be a DSB, HR proficient cells show cisplatin hypersensitivity (Wang et al, 2015).…”

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Replication gaps underlie BRCA-deficiency and therapy response

Panzarino

Krais

Peng

et al. 2019

Preprint

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Cancers that are deficient in BRCA1 or BRCA2 are hypersensitive to genotoxic agents, including platinums and other first-line chemotherapeutics. The established models propose that these cancers are hypersensitive because the chemotherapies block or degrade DNA replication forks and thereby create DNA double strand breaks, both of which require functional BRCA proteins to prevent or resolve by mechanisms termed fork protection (FP) or homologous recombination (HR). However, recent findings challenge this dogma because genotoxic agents do not initially cause DNA double strand breaks or stall replication forks. Here, we propose a new model for genotoxic chemotherapy in which ssDNA replication gaps underlie the hypersensitivity of BRCA deficient cancer, and we propose that defects in HR or FP do not. Specifically, we observed that ssDNA gaps develop in BRCA deficient cells because DNA replication is not effectively restrained in response to genotoxic stress. Moreover, we observe gap suppression (GS) by either restored fork restraint or by gap filling, both of which conferred resistance to therapy in tissue culture and BRCA patient tumors. In contrast, restored HR and FP were not sufficient to prevent hypersensitivity if ssDNA gaps were not eliminated. Together, these data suggest that ssDNA replication gaps underlie the BRCA cancer phenotype, "BRCAness," and we propose are fundamental to the mechanism of action of genotoxic chemotherapies. Introduction:Mutations in the hereditary breast cancer genes, BRCA1 and BRCA2, first demonstrated that cancer is a genetic disease in which susceptibility to cancer could be inherited (King et al., 1986). In addition to breast cancer, mutated BRCA1 or BRCA2 also cause a predisposition to other cancer types, including breast, ovarian, pancreatic, and colorectal cancers. Importantly, cancers with mutated BRCA genes are hypersensitive to cisplatin, a first-line anti-cancer chemotherapy that has been the standard of care for ovarian cancer for over 40 years (Munnell, 1968). BRCA deficient cancers are thought to be

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Fork Protection and Therapy Resistance in Hereditary Breast Cancer

Cited by 19 publications

References 99 publications

Opposing Roles of FANCJ and HLTF Protect Forks and Restrain Replication during Stress

Opposing Roles of FANCJ and HLTF Protect Forks and Restrain Replication during Stress

Replication Gaps Underlie BRCA Deficiency and Therapy Response

Replication gaps underlie BRCA-deficiency and therapy response

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