Available online 7 September 2023, 103569

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Centromeres play a key role in the maintenance of genome stability to prevent carcinogenesis and diseases. They are specialized chromosome loci essential to ensure faithful transmission of genomic information across cell generations by mediating the interaction with spindle microtubules. Nonetheless, while fulfilling these essential roles, their distinct repetitive composition and susceptibility to mechanical stresses during cell division render them susceptible to breakage events. In this review, we delve into the present understanding of the underlying causes of centromere fragility, from the mechanisms governing its DNA replication and repair, to the pathways acting to counteract potential challenges. We propose that the centromere represents a “Trojan horse” exerting vital functions that, at the same time, potentially threatens whole genome stability.

Section snippetsCENTROMERE, THE KEY REGULATOR OF CHROMOSOME SEGREGATION

Centromeres are loci of specialized chromatin serving as assembling point of the kinetochores, which in turn ensure correct attachment of pulling microtubules originating from the spindle pole [1]. Centromeric chromatin is biochemically defined by nucleosomes containing the histone H3 variant CENP-A, a highly conserved protein which allows kinetochore assembly and ensures the epigenetic propagation of centromere identity through cell divisions [2]. CENP-A is directly or indirectly required for

CENTROMERES ARE DAMAGE-PRONE GENOMIC LOCI

Given their distinctive function and complex nature, centromeres are inherently susceptible to a range of challenges that could potentially promote genome instability. Being the docking site for the kinetochore, centromeres must withstand the mechanical forces applied by the spindle microtubules during mitosis [17]. Altered microtubule dynamics and dysregulated kinetochore binding are well-known sources of chromosomal instability [18]. Indeed, prolonged microtubule pulling can enhance

DNA REPLICATION, A TENSE TIME FOR CENTROMERES

Owing to its repetitive nature, centromeric DNA harbours complex secondary structures originating from the repetitive elements themselves. These structures pose potential challenges for DNA replication machinery [24]. Such structures (as depicted in Fig. 1) include hairpins, single-stranded DNA, nucleotide mismatches, and misaligned sequences. A notable phenomenon is the formation of R-loops – three-stranded nucleic acid structures characterized by the presence of a DNA:RNA hybrid. R-loops can

DNA REPAIR PROTEINS SURVEIL THE CENTROMERIC REGIONS

Based on the events illustrated in the previous paragraphs, it is plausible that basal DNA damage is present at centromere triggering a low, but constant, activity of factors involved in DNA damage repair to maintain centromere integrity and replication fidelity (Fig. 2).

Pioneering proteomics experiments, performed on chromatin reconstitution of BACs containing human centromeric α-satellite DNA with Xenopus laevis egg extracts, have identified DNA damage repair (DDR) proteins, despite the

MECHANISMS AND DYNAMICS OF REPAIR OF DAMAGED CENTROMERES

To maintain genome stability in response to DNA insults, a multitude of specialized pathways for DNA repair are in place, including base excision repair (BER), nucleotide excision repair (NER), mismatch repair (MMR), homologous recombination (HR) and non-homologous end joining (NHEJ) (reviewed in [123]). While the mechanisms of DNA repair at euchromatic regions are relatively well understood, the repair processes within heterochromatic regions, including (peri-)centromeres, remain poorly

CONCLUDING REMARKS

The centromere has captured the attention of many biologists since its initial discovery as the primary site of chromosome constriction and microtubule anchoring. In recent years, we have witnessed remarkable advancements in our comprehension of centromere assembly and sequence, and regulation of its architecture, altogether leading to the recognition that the centromere has a broader role in genome inheritance rather than just being the site for kinetochore assembly. It has now become evident

Declaration of Competing Interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Acknowledgements

D.F. receives salary support from the CNRS and I. Curie. A.S. is funded by ANR-21-CE13-0030.

We thank Cristina Bartocci (I. Curie) for suggestions. We truly apologize to the authors whose contributions in the discussed subjects could not be fully highlighted within this review, primarily due to constraints related to space and the number of references.

DECLARATION OF INTERESTS

The authors declare no competing interests.

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