Comprehensive Mapping of Histone Modifications at DNA Double-Strand Breaks Deciphers Repair Pathway Chromatin Signatures

Clouaire, Thomas; Rocher, Vincent; Lashgari, Anahita; Arnould, Coline; Aguirrebengoa, Marion; Biernacka, Anna; Skrzypczak, Magdalena; Aymard, François; Fongang, Bernard; Dojer, Norbert; Iacovoni, Jason S.; Rowicka, Maga; Ginalski, Krzysztof; Côté, Jacques; Legube, Gaëlle

doi:10.1016/j.molcel.2018.08.020

Cited by 257 publications

(342 citation statements)

References 74 publications

(119 reference statements)

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“…Two studies, which also observe an increase in H3K36me2 at DSB sites, linked this increase to the removal of histone demethylases from the chromatin rather than active methylation (19, 20). In contrast, a recent study did not found any increase in H3K36me2 at a DSB site but found instead an increase in H3K36me3 (21). We recently found that SETMAR N210A mutant was decreasing the bulk level of H3K36me2 by western blot and also observed a decrease of H3K36me3 at some genomic positions, possibly because of a decreased H3K36me2 level which is required by SETD2 for adding the third methyl group (7).…”

Section: Discussioncontrasting

confidence: 56%

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SETMAR functions in illegitimate DNA recombination and non-homologous end joining

Tellier

Chalmers

2018

Preprint

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9In anthropoid primates, SETMAR is a fusion between a methyltransferase gene and a 3 0 domesticated DNA transposase. SETMAR has been found to be involved in several 3 1 cellular functions including regulation of gene expression, DNA integration and DNA 3 2 repair. These functions are thought to be mediated through the histone 3 3 methyltransferase, the DNA binding and the nuclease activities of SETMAR. To better 3 4understand the cellular roles of SETMAR, we generated several U2OS cell lines 3 5 expressing either wild type SETMAR or a truncated or mutated variant. We tested these 3 6 cell lines with in vivo plasmid-based assays to determine the relevance of the different 3 7 domains and activities of SETMAR in DNA integration and repair. We found that 3 8 expressing the SET and MAR domains, but not wild type SETMAR, partially affect DNA 3 9integration and repair. The methyltransferase activity of SETMAR is also needed for an 4 0 efficient DNA repair whereas we did not observe any requirement for the putative 4 1 nuclease activity of SETMAR. Overall, our data support a non-essential function for 4 2

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Section: Discussioncontrasting

confidence: 56%

“…Two other papers linked the increase in H3K36me2 following DSBs to the inhibition of KDM2A and KDM2B, two histone demethylases involved in the removal of H3K36 methylation (19, 20). However, a recent study did not observe an increase in H3K36me2 around DSB sites (21).…”

Section: Introductionmentioning

confidence: 93%

SETMAR functions in illegitimate DNA recombination and non-homologous end joining

Tellier

Chalmers

2018

Preprint

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“…Several chromatin remodelers and modifiers that affect the relative activity of the various DNA repair pathways have been identified, which demonstrated that the correct chromatin conformation in proximity to a DSB is critical to ensure successful DNA repair 25 . These findings have sparked an interest in the role of native chromatin on DNA repair pathway choice [26][27][28] . However, studying the effects of chromatin context on repair pathway choice is not straightforward when using common agents to induce DSBs, such as -irradiation or DNA damaging chemotherapeutics 29 .…”

Section: Introductionmentioning

confidence: 99%

DNA end-resection in highly accessible chromatin produces a toxic break

Berg

Joosten

Kim

et al. 2019

Preprint

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Of all damage occurring to DNA, the double strand break (DSB) is the most toxic lesion. Luckily, cells have developed multiple repair pathways to cope with these lesions. These different pathways compete for the same break, and the location of the break can influence this competition. However, the exact contribution of break location in repair pathway preference is not fully understood. We observe that most breaks prefer classical non-homologous end-joining, whereas some depend on DNA end-resection for their repair.Surprisingly, we find that for a subset of these sites, the activation of resection-dependent repair induces a detrimental DNA damage response. These sites exhibit extensive DNA end-resection due to improper recruitment of 53BP1 and the Shieldin complex due to low levels of H4K20me2. Most of these sites reside in close proximity to DNAseI hypersensitive sites. Compacting or removing these regions reduces extensive DNA end-resection and restores normal repair. Taken together, we found that DSB in open chromatin is highly toxic, due to the improper activity of 53BP1 and Shieldin, resulting in extensive DNA end-resection.

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“…This pattern differs from the replication pattern observed for other known instances of genome re-replication during embryonic development 43 , when cells undergo numerous iterations of entire genome duplication, with S phases and M phases alternating to re-license origins anew after the completion of each replication cycle. Because re-replicated DNA can be more susceptible to damage and breakage, the preferential re-replication of early-replicated DNA can be linked to the observed clustering of DNA breaks in euchromatic regions 53,54 .…”

Section: Discussionmentioning

confidence: 99%

Dynamics of replication origin over-activation

Redon

Utani

et al. 2020

Preprint

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We determined replication patterns in cancer cells in which the controls that normally prevent excess replication were disrupted ("re-replicating cells"). Single-fiber analyses suggested that replication origins were activated at a higher frequency in re-replicating cells. However, nascent strand sequencing demonstrated that re-replicating cells utilized the same pool of potential replication origins as normally replicating cells. Surprisingly, rereplicating cells exhibited a skewed initiation frequency correlating with replication timing.These patterns differed from the replication profiles observed in non-re-replicating cells exposed to replication stress, which activated a novel group of dormant origins not typically activated during normal mitotic growth. Hence, disruption of the molecular interactions that regulates origin initiation can activate two distinct pools of potential replication origins: rereplicating cells over-activate flexible origins while replication stress in normal mitotic growth activates dormant origins.Our previous studies have shown that RepID, a replicator-specific binding protein essential for site-specific initiation of DNA replication in mammalian cells 25 , recruits CRL4 to chromatin in a PCNA-independent manner prior to the onset of S phase and promotes CDT1 degradation.RepID deficiency is associated with delayed CDT1 degradation, resulting in limited genome rereplication 26 . Partial genome re-replication can also be caused by inhibition of DOT1L, a methyltransferase which catalyzes the demethylation of histone H3 on lysine 79 (H3K79Me2), thereby removing a histone modification typically associated with a group of replication origins 27 . Because massive re-replication can drive cell death specifically in checkpointcompromised cancer cells, both CDT1 stabilization by inactivation of ubiquitin-mediated degradation and inhibition of DOT1L are currently being explored as novel anti-cancer therapeutic strategies [28][29][30][31][32][33] .Given that genome re-replication is a common avenue to genomic instability and considering its potential as a strategy for chemotherapy, it is important to understand in detail its mechanics and downstream consequences. Here, we report that re-replication exhibits aberrant replication fork dynamics and occurs more slowly than the routine genome duplication that takes place during normal growth. The consequences of the persistent presence of pre-replication complexes on chromatin include massive DNA damage and the induction of senescence. Unlike other instances of replication origin over-activation, such as when replication slows down as a result of nucleotide depletion or in cells exposed to DNA damaging conditions, the re-replication process preferentially utilizes a subset of the replication origin pool typically used during normal growth. Results:

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Comprehensive Mapping of Histone Modifications at DNA Double-Strand Breaks Deciphers Repair Pathway Chromatin Signatures

Cited by 257 publications

References 74 publications

SETMAR functions in illegitimate DNA recombination and non-homologous end joining

SETMAR functions in illegitimate DNA recombination and non-homologous end joining

DNA end-resection in highly accessible chromatin produces a toxic break

Dynamics of replication origin over-activation

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