PARP1 roles in DNA repair and DNA replication: The basi(c)s of PARP inhibitor efficacy and resistance

IF 3 3区 医学 Q2 ONCOLOGY
Petar-Bogomil Kanev, Aleksandar Atemin, Stoyno Stoynov, Radoslav Aleksandrov
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引用次数: 0

Abstract

Genome integrity is under constant insult from endogenous and exogenous sources. In order to cope, eukaryotic cells have evolved an elaborate network of DNA repair that can deal with diverse lesion types and exhibits considerable functional redundancy. PARP1 is a major sensor of DNA breaks with established and putative roles in a number of pathways within the DNA repair network, including repair of single- and double-strand breaks as well as protection of the DNA replication fork. Importantly, PARP1 is the major target of small-molecule PARP inhibitors (PARPi), which are employed in the treatment of homologous recombination (HR)-deficient tumors, as the latter are particularly susceptible to the accumulation of DNA damage due to an inability to efficiently repair highly toxic double-strand DNA breaks. The clinical success of PARPi has fostered extensive research into PARP biology, which has shed light on the involvement of PARP1 in various genomic transactions. A major goal within the field has been to understand the relationship between catalytic inhibition and PARP1 trapping. The specific consequences of inhibition and trapping on genomic stability as a basis for the cytotoxicity of PARP inhibitors remain a matter of debate. Finally, PARP inhibition is increasingly recognized for its capacity to elicit/modulate anti-tumor immunity. The clinical potential of PARP inhibition is, however, hindered by the development of resistance. Hence, extensive efforts are invested in identifying factors that promote resistance or sensitize cells to PARPi. The current review provides a summary of advances in our understanding of PARP1 biology, the mechanistic nature, and molecular consequences of PARP inhibition, as well as the mechanisms that give rise to PARPi resistance.

PARP1 在 DNA 修复和 DNA 复制中的作用:PARP 抑制剂疗效和抗药性的基础
基因组的完整性不断受到来自内源性和外源性的损害。为了应对这种情况,真核细胞进化出了一个复杂的 DNA 修复网络,该网络可以处理各种类型的病变,并具有相当大的功能冗余。PARP1 是 DNA 断裂的主要传感器,在 DNA 修复网络中的许多途径中都扮演着既定和推定的角色,包括单链和双链断裂的修复以及 DNA 复制叉的保护。重要的是,PARP1 是小分子 PARP 抑制剂(PARPi)的主要靶点,PARPi 被用于治疗同源重组(HR)缺陷肿瘤,因为后者因无法有效修复高毒性双链 DNA 断裂而特别容易受到 DNA 损伤的累积。PARPi 在临床上的成功促进了对 PARP 生物学的广泛研究,揭示了 PARP1 参与各种基因组交易的情况。该领域的一个主要目标是了解催化抑制与 PARP1 诱捕之间的关系。作为 PARP 抑制剂细胞毒性的基础,抑制和捕获对基因组稳定性的具体影响仍存在争议。最后,人们越来越认识到 PARP 抑制具有激发/调节抗肿瘤免疫的能力。然而,PARP 抑制剂的临床潜力因耐药性的产生而受到阻碍。因此,人们投入了大量精力来确定促进耐药性或使细胞对 PARPi 敏感的因素。本综述概述了我们对 PARP1 生物学、PARP 抑制的机理性质和分子后果以及产生 PARPi 抗药性的机制的认识进展。
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来源期刊
Seminars in oncology
Seminars in oncology 医学-肿瘤学
CiteScore
6.60
自引率
0.00%
发文量
58
审稿时长
104 days
期刊介绍: Seminars in Oncology brings you current, authoritative, and practical reviews of developments in the etiology, diagnosis and management of cancer. Each issue examines topics of clinical importance, with an emphasis on providing both the basic knowledge needed to better understand a topic as well as evidence-based opinions from leaders in the field. Seminars in Oncology also seeks to be a venue for sharing a diversity of opinions including those that might be considered "outside the box". We welcome a healthy and respectful exchange of opinions and urge you to approach us with your insights as well as suggestions of topics that you deem worthy of coverage. By helping the reader understand the basic biology and the therapy of cancer as they learn the nuances from experts, all in a journal that encourages the exchange of ideas we aim to help move the treatment of cancer forward.
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