Abstract
Accurate and complete genome replication is a fundamental cellular process for the proper transfer of genetic material to cell progenies, normal cell growth, and genome stability. However, a plethora of extrinsic and intrinsic factors challenge individual DNA replication forks and cause replication stress (RS), a hallmark of cancer. When challenged by RS, cells deploy an extensive range of mechanisms to safeguard replicating genomes and limit the burden of DNA damage. Prominent among those is homologous recombination (HR). Although fundamental to cell division, evidence suggests that cancer cells exploit and manipulate these RS responses to fuel their evolution and gain resistance to therapeutic interventions. In this review, we focused on recent insights into HR-mediated protection of stress-induced DNA replication intermediates, particularly the repair and protection of daughter strand gaps (DSGs) that arise from discontinuous replication across a damaged DNA template. Besides mechanistic underpinnings of this process, which markedly differ depending on the extent and duration of RS, we highlight the pathophysiological scenarios where DSG repair is naturally silenced. Finally, we discuss how such pathophysiological events fuel rampant mutagenesis, promoting cancer evolution, but also manifest in adaptative responses that can be targeted for cancer therapy.
Highlights
Accurate and timely propagation of genetic information across multiple generations of dividing cells is a fundamental process initiated by DNA replication and completed by segregation of intact and complete copies of the genome to the progeny [1,2]
After these seminal discoveries, other cancer types and cancer susceptibility genetic diseases, such as Ataxia Telangiectasia, Nijmegen breakage syndrome, Bloom syndrome, and Fanconi anemia (FA), showed a strong correlation to the germline mutations in several other homologous recombination (HR) proteins engaged in HR or functional mutations of single genes that result in hyper- or hypo-recombination phenotypes [26,27]
In the synthesis-dependent strand annealing (SDSA) sub-pathway, which is the predominant pathway in somatic cells, the nascent DNA strand is displaced from the D-loop and subsequently anneals with the second end of the double-strand break (DSB) to resolve as a non-crossover product [47] (Figure 1)
Summary
Accurate and timely propagation of genetic information across multiple generations of dividing cells is a fundamental process initiated by DNA replication and completed by segregation of intact and complete copies of the genome to the progeny [1,2]. The plasticity of replisomes spanning acute responses to various forms of sub-lethal replication perturbations and the role of replication checkpoints have been recently covered in excellent review articles [5,6,8,9,10,11]. In this manuscript, we set out to complement these by discussing the unifying role of replication-coupled homologous recombination (HR) as a key DNA repair mechanism that constantly surveys replicating genomes in human somatic cells. We discussed the cellular context and the pathological outcome of impaired HR-mediated DSG repair in fueling cancer adaptive responses during early stages of cancer evolution and as a response to cancer therapy
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