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Retinoblastoma family proteins: New players in DNA repair by non-homologous end-joining.

ABSTRACT: Loss of retinoblastoma protein (RB1) function is a major driver in cancer development. We have recently reported that, in addition to its well-documented functions in cell cycle and fate control, RB1 and its paralogs have a novel role in regulating DNA repair by non-homologous end joining (NHEJ). Here we summarize our findings and present mechanistic hypotheses on how RB1 may support the DNA repair process and the therapeutic implications for patients who harbor RB1-negative cancers.

SUBMITTER: Huang PH

PROVIDER: S-EPMC4905371 | biostudies-literature | 2016 Mar

REPOSITORIES: biostudies-literature

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Retinoblastoma family proteins: New players in DNA repair by non-homologous end-joining.

Huang Paul H PH Cook Rebecca R Zoumpoulidou Georgia G Luczynski Maciej T MT Mittnacht Sibylle S

Molecular & cellular oncology 20150610 2

Loss of retinoblastoma protein (RB1) function is a major driver in cancer development. We have recently reported that, in addition to its well-documented functions in cell cycle and fate control, RB1 and its paralogs have a novel role in regulating DNA repair by non-homologous end joining (NHEJ). Here we summarize our findings and present mechanistic hypotheses on how RB1 may support the DNA repair process and the therapeutic implications for patients who harbor RB1-negative cancers. ...[more]

PMID: 27308588

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Project description:Simple Summary Cancer onset and progression lead to a high rate of DNA damage, due to replicative and metabolic stress. To survive in this dangerous condition, cancer cells switch the DNA repair machinery from faithful systems to error-prone pathways, strongly increasing the mutational rate that, in turn, supports the disease progression and drug resistance. Although DNA repair de-regulation boosts genomic instability, it represents, at the same time, a critical cancer vulnerability that can be exploited for synthetic lethality-based therapeutic intervention. We here discuss the role of the error-prone DNA repair, named Alternative Non-Homologous End Joining (Alt-NHEJ), as inducer of genomic instability and as a potential therapeutic target. We portray different strategies to drug Alt-NHEJ and discuss future challenges for selecting patients who could benefit from Alt-NHEJ inhibition, with the aim of precision oncology. Abstract Error-prone DNA repair pathways promote genomic instability which leads to the onset of cancer hallmarks by progressive genetic aberrations in tumor cells. The molecular mechanisms which foster this process remain mostly undefined, and breakthrough advancements are eagerly awaited. In this context, the alternative non-homologous end joining (Alt-NHEJ) pathway is considered a leading actor. Indeed, there is experimental evidence that up-regulation of major Alt-NHEJ components, such as LIG3, PolQ, and PARP1, occurs in different tumors, where they are often associated with disease progression and drug resistance. Moreover, the Alt-NHEJ addiction of cancer cells provides a promising target to be exploited by synthetic lethality approaches for the use of DNA damage response (DDR) inhibitors and even as a sensitizer to checkpoint-inhibitors immunotherapy by increasing the mutational load. In this review, we discuss recent findings highlighting the role of Alt-NHEJ as a promoter of genomic instability and, therefore, as new cancer’s Achilles’ heel to be therapeutically exploited in precision oncology.

Dataset Information

Retinoblastoma family proteins: New players in DNA repair by non-homologous end-joining.

Publications

Retinoblastoma family proteins: New players in DNA repair by non-homologous end-joining.

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