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

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.

Keywords

• Personalised Cancer Treatment
• Homologues recombination
• PARP Inhibitors
• BRCA1/2
• DNA Damage Response (DDR) Mechanism
• DNA Hasar Yanıt (DDR) Mekanizması

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

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.

Keywords

• Kişiselleştirilmiş Kanser Tedavisi
• Homolog Rekombinasyon
• PARP İnhibitörleri
• BRCA1/2
• DNA Hasar Yanıt (DDR) Mekanizması

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