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WRN regulates pathway choice between classical and alternative non-homologous end joining.

ABSTRACT: Werner syndrome (WS) is an accelerated ageing disorder with genomic instability caused by WRN protein deficiency. Many features seen in WS can be explained by the diverse functions of WRN in DNA metabolism. However, the origin of the large genomic deletions and telomere fusions are not yet understood. Here, we report that WRN regulates the pathway choice between classical (c)- and alternative (alt)-nonhomologous end joining (NHEJ) during DNA double-strand break (DSB) repair. It promotes c-NHEJ via helicase and exonuclease activities and inhibits alt-NHEJ using non-enzymatic functions. When WRN is recruited to the DSBs it suppresses the recruitment of MRE11 and CtIP, and protects the DSBs from 5' end resection. Moreover, knockdown of Wrn, alone or in combination with Trf2 in mouse embryonic fibroblasts results in increased telomere fusions, which were ablated by Ctip knockdown. We show that WRN regulates alt-NHEJ and shields DSBs from MRE11/CtIP-mediated resection to prevent large deletions and telomere fusions.

SUBMITTER: Shamanna RA

PROVIDER: S-EPMC5150655 | biostudies-literature | 2016 Dec

REPOSITORIES: biostudies-literature

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WRN regulates pathway choice between classical and alternative non-homologous end joining.

Shamanna Raghavendra A RA Lu Huiming H de Freitas Jessica K JK Tian Jane J Croteau Deborah L DL Bohr Vilhelm A VA

Nature communications 20161206

Werner syndrome (WS) is an accelerated ageing disorder with genomic instability caused by WRN protein deficiency. Many features seen in WS can be explained by the diverse functions of WRN in DNA metabolism. However, the origin of the large genomic deletions and telomere fusions are not yet understood. Here, we report that WRN regulates the pathway choice between classical (c)- and alternative (alt)-nonhomologous end joining (NHEJ) during DNA double-strand break (DSB) repair. It promotes c-NHEJ v ...[more]

PMID: 27922005

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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

WRN regulates pathway choice between classical and alternative non-homologous end joining.

Publications

WRN regulates pathway choice between classical and alternative non-homologous end joining.

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