BRCA1 loss activates cathepsin L–mediated degradation of 53BP1 in breast cancer cells

Grotsky, David A; González-Suárez, Ignacio; Novell, Anna; Neumann, Martín; Yaddanapudi, Sree C.; Croke, Monica; Martínez-Alonso, Montserrat; Redwood, Abena B.; Ortega-Martínez, Sylvia; Feng, Zhihui; Lerma, Enrique; Cajal, Teresa Ramón y; Zhang, Junran; Matías‐Guiu, Xavier; Dusso, Adriana; Gonzalo, Susana

doi:10.1083/jcb.201204053

Cited by 71 publications

(88 citation statements)

References 56 publications

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“…The endosomal/lysosomal protease Cathepsin L cleaves 53BP1, especially in the absence of A-type lamins (44). Here we provided insights that phosphorylation of 53BP1 is involved in its degradation.…”

Section: Discussionmentioning

confidence: 76%

UbcH7 regulates 53BP1 stability and DSB repair

Han¹,

Zhang²,

Chung³

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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DNA double-strand break (DSB) repair is not only key to genome stability but is also an important anticancer target. Through an shRNA library-based screening, we identified ubiquitin-conjugating enzyme H7 (UbcH7, also known as Ube2L3), a ubiquitin E2 enzyme, as a critical player in DSB repair. UbcH7 regulates both the steady-state and replicative stress-induced ubiquitination and proteasome-dependent degradation of the tumor suppressor p53-binding protein 1 (53BP1). Phosphorylation of 53BP1 at the N terminus is involved in the replicative stress-induced 53BP1 degradation. Depletion of UbcH7 stabilizes 53BP1, leading to inhibition of DSB end resection. Therefore, UbcH7-depleted cells display increased nonhomologous end-joining and reduced homologous recombination for DSB repair. Accordingly, UbcH7-depleted cells are sensitive to DNA damage likely because they mainly used the errorprone nonhomologous end-joining pathway to repair DSBs. Our studies reveal a novel layer of regulation of the DSB repair choice and propose an innovative approach to enhance the effect of radiotherapy or chemotherapy through stabilizing 53BP1.DNA damage response | UbcH7 | 53BP1 | protein degradation | DSB repair P rompt response to double-strand breaks (DSBs) caused by, for example, ionization radiation (IR), requires sequential and coordinated assembly of DNA damage response (DDR) proteins at damage sites (1). Recent research findings reveal key roles of the tumor suppressor p53-binding protein 1 (53BP1) and BRCA1 in the decision making of DSB repair. 53BP1, together with Rif1, suppress BRCA1-dependent homologous recombination (HR), thereby promoting nonhomologous end-joining (NHEJ) in G1 phase (2-6). Conversely, BRCA1 antagonizes 53BP1/Rif1, favoring HR in S and G2 phases (7,8). In the absence of BRCA1 or with enhanced retention of 53BP1 at DSB sites, cells primarily use the error-prone NHEJ to repair DSBs throughout the cell cycle, which leads to gene rearrangement, cell death, and increased sensitivity to anticancer therapies (9-11). Consistently, BRCA1-null mice are early embryonic lethal (12, 13) and codepletion of TP53BP1 rescued the lethality phenotype of BRCA1-null mice (12)(13)(14).Low expression level of 53BP1 was found to be associated with poor clinical outcome in triple negative breast cancer patients with BRCA1 mutation (12, 15), as well as resistance to genotoxins and poly(ADP-ribose) polymerase inhibitors (12,16,17). This finding is probably because loss of 53BP1 restored HR and promoted cell survival (12-14). Reduced expression of 53BP1 was also observed in tumors from the brain (18), lymph node (19), and pancreas (20). These data indicate that loss of 53BP1 might be a common mechanism for advanced tumors to evade from radiotherapy or chemotherapy. However, molecular mechanisms controlling the protein level of 53BP1 remain less well understood.Here we show that UbcH7, an E2 enzyme involved in the ubiquitin (Ub) pathway, controls the protein stability of 53BP1, thereby determining the DSB repair choice. Loss of UbcH7 sta...

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Section: Discussionmentioning

confidence: 76%

UbcH7 regulates 53BP1 stability and DSB repair

Han¹,

Zhang²,

Chung³

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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“…Cell lines transformed by certain oncogenes, including ras, are known to express high levels of CTSL [12][13][14] . Thus, the upregulation of CTSL is recognized as a hallmark of metastatic cancers and could be utilized as a prognostic marker 9,10,11,15,16 . Recently, nuclear-localized CTSL involved in cancer has been revealed, suggesting that CTSL may have key roles in the nucleus beyond its known lysosomal and extracellular activities 11,[16][17][18][19] .…”

mentioning

confidence: 99%

“…Thus, the upregulation of CTSL is recognized as a hallmark of metastatic cancers and could be utilized as a prognostic marker 9,10,11,15,16 . Recently, nuclear-localized CTSL involved in cancer has been revealed, suggesting that CTSL may have key roles in the nucleus beyond its known lysosomal and extracellular activities 11,[16][17][18][19] . Although the therapeutic potential of CTSL inhibitors has not been fully characterized in preclinical studies, targeting CTSL activity is considered as a strategy for anticancer therapy 20 .…”

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confidence: 99%

Selective cancer targeting with prodrugs activated by histone deacetylases and a tumour-associated protease

et al. 2013

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Eradication of cancer cells while minimizing damage to healthy cells is a primary goal of cancer therapy. Highly selective drugs are urgently needed. Here we demonstrate a new prodrug strategy for selective cancer therapy that utilizes increased histone deacetylase (HDAC) and tumour-associated protease activities produced in malignant cancer cells. By coupling an acetylated lysine group to puromycin, a masked cytotoxic agent is created, which is serially activated by HDAC and an endogenous protease cathepsin L (CTSL) that remove the acetyl group first and then the unacetylated lysine group liberating puromycin. The agent selectively kills human cancer cell lines with high HDAC and CTSL activities. In vivo studies confirm tumour growth inhibition in prodrug-treated mice bearing human cancer xenografts. This cancer-selective cleavage of the masking group is a promising strategy for the next generation of anticancer drug development that could be applied to many other cytotoxic agents.

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“…Yapılan bir derleme çalışmasında kandaki yüksek D vitamini değerleri, pankreas kanseri riskinde artışla ilişkili bulunmuştur (16). 10 yıldan fazla devam eden geniş çaplı bir başka araştırmada da; D vitamininin agresif meme kanserinden korunmada etkili olduğu, yetersiz D vitamini seviyesinin birçok kanser türünde riski artırdığı gösterilmiş-tir (17). Fakat yaklaşık 5500 menapoz sonrası kadın katılım-cıyla, 2013'te yapılan bir başka çalışmada da; D vitamini alımının meme kanseriyle bir ilişkisi bulunamamıştır (18).…”

Section: Vitamininin Kanserden Koruduğu Düşüncesi Nereden Gelmiştir?unclassified

D Vitamini ve Kanserden Korunma

Ünlü¹,

Kirca²,

Öğretmen³

et al. 2016

Akd Med J

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ÖzD vitamini, esas olarak kemik sağlığı için gerekli olmakla birlikte vücutta birçok olayda rol oynayan, yağda çözünen vitaminler grubundan bir bileşiktir. Güneşten gelen ultraviyole ışınlarına maruziyet sonucu vücutta endojen olarak üretilebilen D vitamini, aynı zamanda bazı besinlerde doğal olarak bulunmakta veya D vitamini takviyelerinden elde edilebilmektedir. D vitamini uzun yıllardır bilinen görevlerinin yanı sıra, son yıllarda kanser, diyabet, kalp hastalıkları gibi bazı hastalıklardan korunmadaki etkisiyle de sıkça gündeme gelmektedir. Yapılan bazı araştırmalarda; güneşe maruziyetin az olduğu bölgelerde bazı kanser türlerinin daha sık görüldüğünün gözlenmesi, D vitamininin kanserden korunmada etkili olduğu düşüncesini doğurmuştur. Yapılan laboratuvar çalışmalarında, D vitamininin kanserden korunmada etkili olabileceğine dair güçlü kanıtlar elde edilse de; randomize klinik çalışmaların sonuçları çelişkilidir. D vitamini; hangi dozlarda yararlı, hangi dozlarda zararlı, hangi kanser türlerinde etkili, net olarak bilinmemektedir. Bu noktada, iyi tasarlanmış kapsamlı çalışmalara ihtiyaç vardır. Yapılacak çalışmalar için anahtar; bazı kanser türlerinin riskini azaltan, ancak diğerlerinin riskini artırmayan ideal D vitamini miktarının belirlenmesi olacaktır. Anahtar Sözcükler: D vitamini, Kanser, Kanserden korunma, Kemoprevensiyon AbStrActVitamin D is essential for bone health, and is a compound in the group of fat-soluble vitamins, which plays a role in many events in the body. Vitamin D can be produced as an endogenous substance in the body as a result of exposure to ultraviolet radiation coming from the sun and is also available in certain natural foods or can be obtained from vitamin D supplements. Besides its duties that have been known for years, Vitamin D has been of interest in recent years due to its role in protection against some diseases such as cancer, diabetes, and heart disease. The idea that vitamin D is effective in protection against cancer was born as a result of the fact that certain types of cancer were observed to be more commonly encountered in regions where sun exposure was low in some studies. Although strong evidence has been obtained that vitamin D is likely to be effective in protection from cancer, the results of randomized clinical studies are inconsistent. Vitamin Dʼs beneficial and harmful doses, and the types of cancer on which it is effective, are not clearly known. At this point, well-designed comprehensive studies are needed. The key for the further studies will be the determination of the ideal amount of vitamin D that will reduce the risk of some cancers but will not increase the risk of some others.

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BRCA1 loss activates cathepsin L–mediated degradation of 53BP1 in breast cancer cells

Abstract: Cathepsin L degrades 53BP1 to overcome genomic instability and growth arrest in BRCA1-deficient and triple-negative breast cancers.

Cited by 71 publications

References 56 publications

UbcH7 regulates 53BP1 stability and DSB repair

UbcH7 regulates 53BP1 stability and DSB repair

Selective cancer targeting with prodrugs activated by histone deacetylases and a tumour-associated protease

D Vitamini ve Kanserden Korunma

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