Activation of homologous recombination in G1 preserves centromeric integrity

Yilmaz, Duygu; Furst, Audrey; Meaburn, Karen J.; Lezaja, Aleksandra; Wen, Yanlin; Altmeyer, Matthias; Reina‐San‐Martin, Bernardo; Soutoglou, Evi

doi:10.1038/s41586-021-04200-z

Cited by 64 publications

(72 citation statements)

References 51 publications

(59 reference statements)

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“…The global chromatin mobility observed in different regions of the nucleus could thus be a way to coordinate different responses to DNA damage. The proximal mobility observed in the pericentromeric region, in particular, may be an additional means of ensuring the essential maintenance of centromeres (Yilmaz et al 2021). Interestingly, a sophisticated biological function such as sleep has been associated with chromosome mobility (Zada et al 2019).…”

Section: Discussionmentioning

confidence: 99%

Global chromatin mobility induced by a DSB is dictated by chromosomal conformation and defines the outcome of Homologous Recombination

Fernández

Almayrac

Simon

et al. 2022

Preprint

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Repair of DNA double-strand breaks (DSBs) is crucial for genome integrity. A conserved response to DSBs is an increase in chromatin mobility that can be local, at the site of the DSB, or global, at undamaged regions of the genome. Here we address the function of global chromatin mobility during homologous recombination (HR) of a single, targeted, controlled DSB. We set up a system that tracks HR in vivo over time and show that two types of DSB-induced global chromatin mobility are involved in HR, depending on the position of the DSB. In spatial proximal regions such as the pericentromeric region, a DSB therein induces global mobility that depends solely on H2A(X) phosphorylation and accelerates repair kinetics, but is not essential. In contrast, the global mobility induced by a DSB away from the centromere, becomes essential for HR repair and is triggered by homology search through a mechanism that depends on H2A(X) phosphorylation, checkpoint progression and Rad51. Our data demonstrate that global mobility is governed by chromosomal conformation and differentially coordinates repair by HR.

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Section: Discussionmentioning

confidence: 99%

Global chromatin mobility induced by a DSB is dictated by chromosomal conformation and defines the outcome of Homologous Recombination

Fernández

Almayrac

Simon

et al. 2022

Preprint

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“…In human cells, two pathways, HDR and NHEJ, take part in DNA DSBs repair ( Chang et al, 2017 ). HDR is generally considered to be participated in DSBs repair only during the S and G2 phases of the cell cycle given that it needs a homologous template to replace the damaged DNA segment in the genome, but it has been shown that centromeric DSBs in the G1 phase can activate the HDR pathway to maintain centromeric integrity recently ( Yilmaz et al, 2021 ). The canonical HDR pathway is relatively slow but error-free, which needs numerous factors involved in homology search, Holliday junction formation, DNA synthesis, and the final DNA ligation ( San Filippo et al, 2008 ; Krejci et al, 2012 ).…”

Section: Overview Of Dna Damage and Repair Networkmentioning

confidence: 99%

Nucleic Acid Sensing Pathways in DNA Repair Targeted Cancer Therapy

Xie

Luo

2022

Front. Cell Dev. Biol.

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The repair of DNA damage is a complex process, which helps to maintain genome fidelity, and the ability of cancer cells to repair therapeutically DNA damage induced by clinical treatments will affect the therapeutic efficacy. In the past decade, great success has been achieved by targeting the DNA repair network in tumors. Recent studies suggest that DNA damage impacts cellular innate and adaptive immune responses through nucleic acid-sensing pathways, which play essential roles in the efficacy of DNA repair targeted therapy. In this review, we summarize the current understanding of the molecular mechanism of innate immune response triggered by DNA damage through nucleic acid-sensing pathways, including DNA sensing via the cyclic GMP-AMP synthase (cGAS), Toll-like receptor 9 (TLR9), absent in melanoma 2 (AIM2), DNA-dependent protein kinase (DNA-PK), and Mre11-Rad50-Nbs1 complex (MRN) complex, and RNA sensing via the TLR3/7/8 and retinoic acid-inducible gene I (RIG-I)-like receptors (RLRs). Furthermore, we will focus on the recent developments in the impacts of nucleic acid-sensing pathways on the DNA damage response (DDR). Elucidating the DDR-immune response interplay will be critical to harness immunomodulatory effects to improve the efficacy of antitumor immunity therapeutic strategies and build future therapeutic approaches.

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“…Further, NHEJ proteins that do not form foci in response to IR are detectable in response to Cas9-induced breaks, given that the large amount of damage in the satellite amplifies the signal. Other repeated sequences can be targeted with similar approaches, including centromeres [ 12 , 89 ] or rDNA [ 90 , 91 , 92 ], enabling the exploration of several domains characterized by repeated DNAs.…”

Section: Approaches To Study Heterochromatic Dsb Responsesmentioning

confidence: 99%

An Expanding Toolkit for Heterochromatin Repair Studies

Rawal

Butova

Mitra

et al. 2022

Genes

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Pericentromeric heterochromatin is mostly composed of repetitive DNA sequences prone to aberrant recombination. Cells have developed highly specialized mechanisms to enable ‘safe’ homologous recombination (HR) repair while preventing aberrant recombination in this domain. Understanding heterochromatin repair responses is essential to understanding the critical mechanisms responsible for genome integrity and tumor suppression. Here, we review the tools, approaches, and methods currently available to investigate double-strand break (DSB) repair in pericentromeric regions, and also suggest how technologies recently developed for euchromatin repair studies can be adapted to characterize responses in heterochromatin. With this ever-growing toolkit, we are witnessing exciting progress in our understanding of how the ‘dark matter’ of the genome is repaired, greatly improving our understanding of genome stability mechanisms.

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Activation of homologous recombination in G1 preserves centromeric integrity

Abstract: H3K4me2 promotes HR at centromeric DSBsCentromeres are considered to be part of heterochromatin, yet they are transcribed and contain active chromatin marks, such as H3K4me2 12,13 .

Cited by 64 publications

References 51 publications

Global chromatin mobility induced by a DSB is dictated by chromosomal conformation and defines the outcome of Homologous Recombination

Global chromatin mobility induced by a DSB is dictated by chromosomal conformation and defines the outcome of Homologous Recombination

Nucleic Acid Sensing Pathways in DNA Repair Targeted Cancer Therapy

An Expanding Toolkit for Heterochromatin Repair Studies

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