2010
DOI: 10.1038/nsmb.1831
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53BP1 loss rescues BRCA1 deficiency and is associated with triple-negative and BRCA-mutated breast cancers

Abstract: Germ-line mutations in BRCA1 predispose to breast and ovarian cancer. BRCA1-mutated tumors show genomic instability, mainly as a consequence of impaired recombinatorial DNA repair. Here we identify 53BP1 as an essential factor for sustaining the growth arrest induced by Brca1 deletion. Depletion of 53BP1 abrogates the ATM-dependent checkpoint response and G2 cell cycle arrest triggered by the accumulation of DNA breaks in Brca1-deleted cells. This effect of 53BP1 is specific to BRCA1 function, as 53BP1 depleti… Show more

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Cited by 877 publications
(965 citation statements)
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References 55 publications
(70 reference statements)
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“…18,19 These studies have placed 53BP1 as a top candidate for pharmacological targeting for future breast cancer therapies. Therefore, we sought to understand whether the impairment of 53BP1 is sufficient to explain the NUP153-deficient phenotype in our DNA repair assays, to suggest NUP153 as a potential candidate for targeted cancer therapy.…”
Section: Resultsmentioning
confidence: 99%
See 1 more Smart Citation
“…18,19 These studies have placed 53BP1 as a top candidate for pharmacological targeting for future breast cancer therapies. Therefore, we sought to understand whether the impairment of 53BP1 is sufficient to explain the NUP153-deficient phenotype in our DNA repair assays, to suggest NUP153 as a potential candidate for targeted cancer therapy.…”
Section: Resultsmentioning
confidence: 99%
“…However, as NUP153 promotes 53BP1 IRIF foci formation after DNA damage, impairment of NUP153 in BRCA1 cancer cells could mimic the phenotype of 53BP1 depletion, rescuing lethality and conferring resistance to PARP inhibition. 18,19 It will be consequently very interesting to exploit in the future the potential of NUP153 as a therapeutic target in certain cancers. were subjected to laser micro-irradiation using a 800-nm laser and subsequent real time recording of protein assembly at the damaged area.…”
Section: Resultsmentioning
confidence: 99%
“…In line with this hypothesis, HP1α knockdown impairs both 53BP1 and BRCA1 recruitment to sites of damage. 17 Given that 53BP1 and BRCA1 have opposite effects on DNA-end resection, [30][31][32][33] further research on this particular issue would certainly be critical to shed light on the molecular details of HP1 role during this process.…”
Section: Discussionmentioning
confidence: 99%
“…Increase in RAD51 Waddell et al, 2009) and HR can rescue growth defects in BRCA1-deficient cells . Furthermore, the depletion of 53BP1 can rescue BRCA1 deficiency by reactivation of ATM-dependent HR pathway (Bouwman et al, 2010;Bunting et al, 2010). Indeed, a remarkable correlation exists between the absence of 53BP1 and the most aggressive and difficult-to-treat triple-negative breast tumors (Bouwman et al, 2010).…”
Section: Arrest/senescencementioning
confidence: 99%
“…Furthermore, the depletion of 53BP1 can rescue BRCA1 deficiency by reactivation of ATM-dependent HR pathway (Bouwman et al, 2010;Bunting et al, 2010). Indeed, a remarkable correlation exists between the absence of 53BP1 and the most aggressive and difficult-to-treat triple-negative breast tumors (Bouwman et al, 2010). In addition, 53BP1 loss could be a likely mechanism of resistance to PARPi.…”
Section: Arrest/senescencementioning
confidence: 99%