Homologous recombination in cancer development, treatment and development of drug resistance.
Thomas Helleday,Thomas Helleday +1 more
TLDR
The diversity of HR and how it impacts on cancer is discussed with a particular focus on how HR can be exploited in future anticancer strategies.Abstract:Â
Although DNA double-strand breaks (DSBs) are substrates for homologous recombination (HR) repair, it is becoming apparent that DNA lesions produced at replication forks, for instance by many anticancer drugs, are more significant substrates for HR repair. Cells defective in HR are hypersensitive to a wide variety of anticancer drugs, including those that do not produce DSBs. Several cancers have mutations in or epigenetically silenced HR genes, which explain the genetic instability that drives cancer development. There are an increasing number of reports suggesting that mutation or epigenetic silencing of HR genes explains the sensitivity of cancers to current chemotherapy treatments. Furthermore, there are also many examples of re-expression of HR genes in tumours to explain drug resistance. Emerging data suggest that there are several different subpathways of HR, which can compensate for each other. Unravelling the overlapping pathways in HR showed that BRCA1- and BRCA2-defective cells rely on the PARP protein for survival. This synthetic lethal interaction is now being exploited for selective treatment of BRCA1- and BRCA2-defective cancers with PARP inhibitors. Here, I discuss the diversity of HR and how it impacts on cancer with a particular focus on how HR can be exploited in future anticancer strategies.read more
Citations
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DNA damage and the balance between survival and death in cancer biology
TL;DR: This Review described key decision-making nodes in the complex interplay between cell survival and death following DNA damage, which determine the outcome of cancer therapy with genotoxic drugs.
Journal ArticleDOI
Human RecQ helicases in DNA repair, recombination, and replication.
TL;DR: Future research goals in this field include a better understanding of the division of labor among the human Rec Q helicases and learning how human RecQ helicases collaborate and cooperate to enhance genome stability.
Journal ArticleDOI
Induction and repair of DNA double strand breaks: the increasing spectrum of non-homologous end joining pathways.
Emil Mladenov,George Iliakis +1 more
TL;DR: Mechanisms of DSB induction by IR are outlined and particular emphasis on backup pathways of NHEJ are placed on and summarized their increasing significance in various cellular processes, as well as their potential contribution to carcinogenesis.
Journal ArticleDOI
Mre11-dependent degradation of stalled DNA replication forks is prevented by BRCA2 and PARP1.
TL;DR: Increased levels of Mre11 activity are shown, a key component of MRN (Mre11-Rad50-Nbs1) complex that plays a role in the restart of stalled replication forks and enhanced resection at stalled replication fork in BRCA2-deficient cells, which offers insight into the molecular mechanisms of the synthetic lethality between BRC a2 and PARP1.
Journal ArticleDOI
The aneuploidy paradox: costs and benefits of an incorrect karyotype
Jason M. Sheltzer,Angelika Amon +1 more
TL;DR: New models of aneuploidy and chromosomal instability have shed light on the diverse effects that karyotypic imbalances have on cellular phenotypes, and suggest novel ways of understanding the role of anneuploids in development and disease.
References
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