Centromeres as universal hotspots of DNA breakage, driving RAD51-mediated recombination during quiescence

Saayman, Xanita; Graham, Emily B.; Nathan, William J.; Nussenzweig, André; Esashi, Fumiko

doi:10.1016/j.molcel.2023.01.004

Cited by 28 publications

(20 citation statements)

References 62 publications

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“…Failure to relocate engages repair of the breaks through RAD52-dependent single-strand annealing, which uses homologous repeats to bridge DSB ends but causes deletions and rearrangements between the repeats ( 61 , 62 ). Along with the observation by the Esashi group that RAD51 depletion leads to a loss of CENP-A in both quiescent and cycling cells ( 59 ), this work demonstrates that recombination events can be beneficial for centromere stability. It also brings evidence that centromeric heterochromatin is not refractory to repair when it comes to DSB induction.…”

Section: Centromeres Are Sources Of Genome Instability and Tumorigenesissupporting

confidence: 76%

“…Spontaneous DNA breaks within the centromere have been mainly attributed to active DNA replication. However, a new study has recently highlighted that they can also be induced de novo during quiescence ( 59 ). These breaks were initiated by topoisomerase IIβ activity and resolved by RAD51 recombinase.…”

Section: Centromeres Are Sources Of Genome Instability and Tumorigenesismentioning

confidence: 99%

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Molecular mechanisms protecting centromeres from self-sabotage and implications for cancer therapy

2023

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Centromeres play a crucial role in DNA segregation by mediating the cohesion and separation of sister chromatids during cell division. Centromere dysfunction, breakage or compromised centromeric integrity can generate aneuploidies and chromosomal instability, which are cellular features associated with cancer initiation and progression. Maintaining centromere integrity is thus essential for genome stability. However, the centromere itself is prone to DNA breaks, likely due to its intrinsically fragile nature. Centromeres are complex genomic loci that are composed of highly repetitive DNA sequences and secondary structures and require the recruitment and homeostasis of a centromere-associated protein network. The molecular mechanisms engaged to preserve centromere inherent structure and respond to centromeric damage are not fully understood and remain a subject of ongoing research. In this article, we provide a review of the currently known factors that contribute to centromeric dysfunction and the molecular mechanisms that mitigate the impact of centromere damage on genome stability. Finally, we discuss the potential therapeutic strategies that could arise from a deeper understanding of the mechanisms preserving centromere integrity.

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Section: Centromeres Are Sources Of Genome Instability and Tumorigenesissupporting

confidence: 76%

Section: Centromeres Are Sources Of Genome Instability and Tumorigenesismentioning

confidence: 99%

Molecular mechanisms protecting centromeres from self-sabotage and implications for cancer therapy

2023

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“…This loading prevents centromeric instability and chromosomal rearrangements mediated by SSA and POL theta-mediated A-EJ [ 47 ]. In the same manner, RAD51 was shown to be recruited at centromeres in quiescent RPE-hTERT cells and to protect centromeres from breakage in a way that requires the strand exchange activity [ 48 ].…”

Section: Noncatalytic Roles Of Rad51 In Dsb Repairmentioning

confidence: 99%

Noncanonical Roles of RAD51

Thomas

Dubacq

Rabut

et al. 2023

Cells

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Homologous recombination (HR), an evolutionary conserved pathway, plays a paramount role(s) in genome plasticity. The pivotal HR step is the strand invasion/exchange of double-stranded DNA by a homologous single-stranded DNA (ssDNA) covered by RAD51. Thus, RAD51 plays a prime role in HR through this canonical catalytic strand invasion/exchange activity. The mutations in many HR genes cause oncogenesis. Surprisingly, despite its central role in HR, the invalidation of RAD51 is not classified as being cancer prone, constituting the “RAD51 paradox”. This suggests that RAD51 exercises other noncanonical roles that are independent of its catalytic strand invasion/exchange function. For example, the binding of RAD51 on ssDNA prevents nonconservative mutagenic DNA repair, which is independent of its strand exchange activity but relies on its ssDNA occupancy. At the arrested replication forks, RAD51 plays several noncanonical roles in the formation, protection, and management of fork reversal, allowing for the resumption of replication. RAD51 also exhibits noncanonical roles in RNA-mediated processes. Finally, RAD51 pathogenic variants have been described in the congenital mirror movement syndrome, revealing an unexpected role in brain development. In this review, we present and discuss the different noncanonical roles of RAD51, whose presence does not automatically result in an HR event, revealing the multiple faces of this prominent actor in genomic plasticity.

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“…Mammalian cells have two Top2 isoenzymes, Top2α and Top2β [ 35 ]. Top2α is associated with DNA replication and, as a consequence, cell proliferation, while Top2β may play a role in transcription [ 39 , 41 ].…”

Section: Irinotecan’s Mode Of Actionmentioning

confidence: 99%

Resistance to TOP-1 Inhibitors: Good Old Drugs Still Can Surprise Us

Kumar

Sherman

2023

IJMS

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Irinotecan (SN-38) is a potent and broad-spectrum anticancer drug that targets DNA topoisomerase I (Top1). It exerts its cytotoxic effects by binding to the Top1-DNA complex and preventing the re-ligation of the DNA strand, leading to the formation of lethal DNA breaks. Following the initial response to irinotecan, secondary resistance is acquired relatively rapidly, compromising its efficacy. There are several mechanisms contributing to the resistance, which affect the irinotecan metabolism or the target protein. In addition, we have demonstrated a major resistance mechanism associated with the elimination of hundreds of thousands of Top1 binding sites on DNA that can arise from the repair of prior Top1-dependent DNA cleavages. Here, we outline the major mechanisms of irinotecan resistance and highlight recent advancements in the field. We discuss the impact of resistance mechanisms on clinical outcomes and the potential strategies to overcome resistance to irinotecan. The elucidation of the underlying mechanisms of irinotecan resistance can provide valuable insights for the development of effective therapeutic strategies.

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Centromeres as universal hotspots of DNA breakage, driving RAD51-mediated recombination during quiescence

Cited by 28 publications

References 62 publications

Molecular mechanisms protecting centromeres from self-sabotage and implications for cancer therapy

Molecular mechanisms protecting centromeres from self-sabotage and implications for cancer therapy

Noncanonical Roles of RAD51

Resistance to TOP-1 Inhibitors: Good Old Drugs Still Can Surprise Us

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