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Defektif Homolog Rekombinasyon DNA Tamiri ve PARP İnhibisyonu Arasındaki Sentetik Letal Etkileşim

Year 2022, Volume: 12 Issue: 4, 2459 - 2475, 01.12.2022
https://doi.org/10.21597/jist.1095366

Abstract

İnsan hücreleri endojen ve eksojen nedenlerle oluşan genomik hasarlara karşı kompleks bir DNA hasar yanıt
mekanizmasına sahiptir. Hücreler, DNA hasar yanıt işlevsizliği durumunda onarılmadıklarından genom stabilitesini tehdit
eden çeşitli DNA lezyonlarını biriktirmeye başlar. Yetersiz DNA hasar yanıt aktivitesi; neoplastik transformasyona, antikanser ilaç direncine ve ilgili tedaviler neticesinde oluşan ciddi yan etkilere neden olmanın yanı sıra, tedavi yanıtının
tahmininde kullanılabilir bir biyogösterge veya kanser hücrelerini mevcut tedavilere karşı daha duyarlı hale getirebilecek
farmakolojik bir hedef olarak da kullanılabilmektedir. Poli (ADP-riboz) (PARP) enzimleri, DNA tek zincir kırıklarının
onarılması dahil birçok hücresel mekanizmada rol oynamaktadır. BRCA1/2 proteinleri ise DNA çift zincir kırıklarının
homolog rekombinasyon yolağıyla tamir edilmesinde görev almaktadır. Yapılan çalışmalar, BRCA1/2 mutasyonu
neticesinde homolog rekombinasyon defektif hale gelen hücrelerin PARP inhibitörlerine karşı hassasiyet kazandığı
göstermiştir. BRCA1/2 ve PARP arasında tanımlanan söz konusu sentetik letal etkileşimin başarılı klinik uygulaması,
araştırmacıları homolog rekombinasyon durumunu bildirecek farklı biyogöstergeleri araştırmaya ve PARP inhibitör
direncinin üstesinden gelmek için diğer potansiyel sentetik letal etkileşimleri ortaya çıkarmaya yönlendirmiştir. Bu
derlemede öncelikle DNA hasar yanıt yolağının mevcut durumu özetlenmiş, sonrasında HR tamir sistemi ve PARP
inhibisyonu arasındaki sentetik letalite anlatılmıştır.

Supporting Institution

TÜBİTAK

Project Number

119S007

Thanks

Bingöl Üniversitesi Kanser Araştırma Laboratuvarı'nda gerçekleştirilen çalışmalar TÜBİTAK (proje numaraları: 119S007, 218S877 ve 120S774) ve Bingöl Üniversitesi (proje numaraları: BAP-SHMYO.2019.00.002 ve BAP-FEF-2021.008) tarafından desteklenmektedir. Yazarlar tüm laboratuvar üyelerine katkılarından dolayı teşekkür eder.

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Synthetic Lethal Interaction between Defective Homologous Recombination DNA Repair and PARP Inhibition

Year 2022, Volume: 12 Issue: 4, 2459 - 2475, 01.12.2022
https://doi.org/10.21597/jist.1095366

Abstract

Human cells are equipped with a complex DNA damage response mechanism to deal with endogenously or
exogenously induced genome damages. In the case of impaired DNA damage response functionality, cells start
accumulating various DNA lesions which, if not repaired, threat genome stability. Although inefficient DNA damage
response activity can promote neoplastic transformation, anti-cancer treatment resistance and serious side effects, any
specific DDR dysfunctionality could serve as a biomarker to predict therapeutic response or a pharmacologic target to
render cancer cells more vulnerable to chemotherapeutics. Poly (ADP-ribose) (PARP) enzymes participate in various
cellular processes, including DNA single-strand break repair pathway. BRCA1/2 proteins play essential roles in
homologous recombination DNA double-strand break repair pathway. Recent studies showed that cells with homologous
recombination deficiency due to BRCA1/2 mutations become sensitive to PARP inhibitors. The successful clinical
implementation of the synthetic lethal interaction between BRCA1/2 and PARP has motivated researchers to investigate
other possible biomarkers to evaluate homologous recombination efficiency and untangle other potential synthetic lethal
interactions to overcome PARP inhibitor resistance. In this review, we first summarize the current understanding of DNA
damage response activated upon DNA double-strand break formation, then explain the synthetic lethality between
homologous recombination-mediated repair and PARP inhibition.

Project Number

119S007

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There are 138 citations in total.

Details

Primary Language Turkish
Subjects Structural Biology
Journal Section Moleküler Biyoloji ve Genetik / Moleculer Biology and Genetic
Authors

Yusuf Toy 0000-0003-1901-9994

Ramazan Gundogdu 0000-0001-5230-2121

Aydın Sever 0000-0002-6727-1556

Mehmet Kadir Erdoğan 0000-0002-1579-5737

Project Number 119S007
Early Pub Date November 25, 2022
Publication Date December 1, 2022
Submission Date March 29, 2022
Acceptance Date August 9, 2022
Published in Issue Year 2022 Volume: 12 Issue: 4

Cite

APA Toy, Y., Gundogdu, R., Sever, A., Erdoğan, M. K. (2022). Defektif Homolog Rekombinasyon DNA Tamiri ve PARP İnhibisyonu Arasındaki Sentetik Letal Etkileşim. Journal of the Institute of Science and Technology, 12(4), 2459-2475. https://doi.org/10.21597/jist.1095366
AMA Toy Y, Gundogdu R, Sever A, Erdoğan MK. Defektif Homolog Rekombinasyon DNA Tamiri ve PARP İnhibisyonu Arasındaki Sentetik Letal Etkileşim. J. Inst. Sci. and Tech. December 2022;12(4):2459-2475. doi:10.21597/jist.1095366
Chicago Toy, Yusuf, Ramazan Gundogdu, Aydın Sever, and Mehmet Kadir Erdoğan. “Defektif Homolog Rekombinasyon DNA Tamiri Ve PARP İnhibisyonu Arasındaki Sentetik Letal Etkileşim”. Journal of the Institute of Science and Technology 12, no. 4 (December 2022): 2459-75. https://doi.org/10.21597/jist.1095366.
EndNote Toy Y, Gundogdu R, Sever A, Erdoğan MK (December 1, 2022) Defektif Homolog Rekombinasyon DNA Tamiri ve PARP İnhibisyonu Arasındaki Sentetik Letal Etkileşim. Journal of the Institute of Science and Technology 12 4 2459–2475.
IEEE Y. Toy, R. Gundogdu, A. Sever, and M. K. Erdoğan, “Defektif Homolog Rekombinasyon DNA Tamiri ve PARP İnhibisyonu Arasındaki Sentetik Letal Etkileşim”, J. Inst. Sci. and Tech., vol. 12, no. 4, pp. 2459–2475, 2022, doi: 10.21597/jist.1095366.
ISNAD Toy, Yusuf et al. “Defektif Homolog Rekombinasyon DNA Tamiri Ve PARP İnhibisyonu Arasındaki Sentetik Letal Etkileşim”. Journal of the Institute of Science and Technology 12/4 (December 2022), 2459-2475. https://doi.org/10.21597/jist.1095366.
JAMA Toy Y, Gundogdu R, Sever A, Erdoğan MK. Defektif Homolog Rekombinasyon DNA Tamiri ve PARP İnhibisyonu Arasındaki Sentetik Letal Etkileşim. J. Inst. Sci. and Tech. 2022;12:2459–2475.
MLA Toy, Yusuf et al. “Defektif Homolog Rekombinasyon DNA Tamiri Ve PARP İnhibisyonu Arasındaki Sentetik Letal Etkileşim”. Journal of the Institute of Science and Technology, vol. 12, no. 4, 2022, pp. 2459-75, doi:10.21597/jist.1095366.
Vancouver Toy Y, Gundogdu R, Sever A, Erdoğan MK. Defektif Homolog Rekombinasyon DNA Tamiri ve PARP İnhibisyonu Arasındaki Sentetik Letal Etkileşim. J. Inst. Sci. and Tech. 2022;12(4):2459-75.