How cells ensure correct repair of DNA double-strand breaks

Her, Joonyoung; Bunting, Samuel F.

doi:10.1074/jbc.tm118.000371

Cited by 240 publications

(219 citation statements)

References 98 publications

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“…and low affinity BRCA1-BARD1 binding to unreplicated chromatin versus low affinity 53BP1 and high affinity BRCA1-BARD1 binding in replicated chromatin. This view is consistent with supraphysiological 53BP1 accumulation at damaged replicated chromatin 6 in BRCA1-deficient cells 29 , yet it suggests that even in absence of BRCA1-BARD1 the accumulation of 53BP1 is curtailed by reduced H4K20me2 in replicated chromatin. The DDR thus makes use of replication-coupled dilution of an abundant histone mark, which cells only restore in replicated chromatin when genome duplication has been completed, and enforced premature restoration of H4K20me2 during S-phase progression indeed shifts the balance towards a 53BP1-governed response 11 .…”

Section: Resultssupporting

confidence: 71%

“…The balance between non-homologous end-joining (NHEJ) and homologous recombination (HR) has important implications for maintenance of genome stability, for exploiting DNA damage response (DDR) defects as vulnerabilities in cancer therapy, and for harnessing the full potential of CRISPR/Cas9-mediated genome editing and gene therapy [1][2][3] . The choice between NHEJ and HR is closely linked to the cell cycle and to whether or not an undamaged homologous stretch of DNA is available as a template for HR [4][5][6] . While 53BP1-RIF1-Shieldin restrains DNA end resection of DNA double-strand breaks (DSBs) in the absence of a homologous template strand, after DNA replication BRCA1-BARD1 counteracts 53BP1 binding to damaged chromatin and promotes HR reactions [7][8][9][10][11][12] .…”

Section: Introductionmentioning

confidence: 99%

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Replicated chromatin curtails 53BP1 recruitment in BRCA1-proficient and -deficient cells

Mitxelena

Pellegrino

Spegg

et al. 2020

Preprint

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DNA double-strand breaks can be repaired by two competing mechanisms, nonhomologous end-joining (NHEJ) and homologous recombination (HR). Whether one or the other repair pathway is favored depends on the availability of an undamaged template DNA that allows for homology-directed repair. The tumor suppressor proteins 53BP1 and BRCA1 are considered antagonistic players in this repair pathway choice, as 53BP1 restrains DNA end resection, whereas BRCA1, together with its partner protein BARD1, displaces 53BP1 from damaged replicated chromatin and promotes HR. How cells switch from a 53BP1-dominated to a BRCA1-dominated response as they progress through the cell cycle is incompletely understood. Here we reveal, using high-throughput microscopy and applying single cell normalization to control for increased genome size as cells replicate their DNA, that 53BP1 recruitment to damaged replicated chromatin is inefficient in both BRCA1-proficient and BRCA1-deficient cells, in comparison to 53BP1 accumulation at damaged unreplicated chromatin. These findings substantiate a dual switch model from a 53BP1-dominated response in unreplicated chromatin to a BRCA1-BARD1-dominated response in replicated chromatin, in which replication-coupled dilution of 53BP1's binding mark H4K20me2 functionally cooperates with BRCA1-BARD1mediated suppression of 53BP1 binding. More generally, we suggest that appropriate normalization of single cell data, e.g. to DNA content, provides additional layers of information, which can be critical for quantifying and interpreting cellular phenotypes.

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Section: Resultssupporting

confidence: 71%

Section: Introductionmentioning

confidence: 99%

Replicated chromatin curtails 53BP1 recruitment in BRCA1-proficient and -deficient cells

Mitxelena

Pellegrino

Spegg

et al. 2020

Preprint

View full text Add to dashboard Cite

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“…The change in extent of resection could indicate a change in which pathways are being used to repair the DSBs. The difference in DNA end structure at the site of break and the extent of resection in part dictates repair pathway choice between NHEJ, HR, and other pathways such as microhomology-mediated end joining (MMEJ) and single-strand annealing (SSA) [2,3,[24][25][26][27]. While little to no resection and end-processing is supportive of NHEJ, short resection facilitates a shift towards SSA and MMEJ, but a long resection drives completely to HR.…”

Section: Discussionmentioning

confidence: 99%

CNCC: An analysis tool to determine genome-wide DNA break end structure at single-nucleotide resolution

Szlachta

Raimer

Comeau

et al. 2019

Preprint

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DNA double-stranded breaks (DSBs) are potentially deleterious events in a cell. The end structures (blunt, 3'-and 5'-overhangs) at sites of double-stranded breaks contribute to the fate of their repair and provide critical information for consequences of the damage. Here, we describe the use of a coverage-normalized cross correlation analysis (CNCC) to process high-precision genome-wide break mapping data, and determine genome-wide break end structure distributions at single-nucleotide resolution. For the first time, on a genome-wide scale, our analysis revealed the increase in the 5' to 3' end resection following etoposide treatment, and the global progression of the resection due to the removal of DNA topoisomerase II cleavage complexes. Further, our method distinguished the change in the pattern of DSB end structure with increasing doses of the drug. The ability of this method to determine DNA break end structures without a priori knowledge of break sequences or genomic position should have broad applications in understanding genome instability. KeywordsDouble-stranded DNA breaks, DNA break end type, DNA end resection, etoposide treatment, topoisomerase II * * *

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“…The choice of repair pathway between HR and NHEJ and among different subtypes of NHEJ depends on phylogenetic positions, cell cycle phases and chromosomal repetitive contents (Lieber and Karanjawala 2004;Mao, et al 2008;Her and Bunting 2018). If an organism predominantly use HR in its DSB repair, desiccation-induced DSBs do not open the gateway for HGTs and EDTs.…”

Section: Discussionmentioning

confidence: 99%

Desiccation Does Not Drastically Increase the Accessibility of Foreign DNA to the Nuclear Genomes: Evidence from the Frequency of Endosymbiotic DNA Transfer

Fang

Zhao

et al. 2018

Preprint

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Horizontal gene transfer (HGT) is a widely accepted force in the evolution of prokaryotic genomes. However, in eukaryotes, it is still in hot debate. Some bdelloid rotifers that are resistant to extreme desiccation and radiation were reported to have a very high level of HGTs. However, a similar report in another resistant invertebrate, tardigrades, has been mired in controversy. The DNA double-strand breaks (DSBs) induced by prolonged desiccation have been postulated to open the gateway of nuclear genome for foreign DNA integration and thus facilitate the HGT process. If so, the rate of endosymbiotic DNA transfer should also be enhanced. We first surveyed the abundance of nuclear mitochondrial DNAs (NUMTs) and nuclear plastid DNAs (NUPTs) in three groups of eukaryotes that are extremely resistant to desiccation, bdelloid rotifers, A. vaga and A. ricciae, tardigrades, H. dujardini and R. varieornatus, and the resurrection plants, D. hygrometricum and S. tamariscina. Excessive NUMTs or NUPTs have not been detected. Furthermore, we compared nine groups of desiccation-tolerant organisms with their desiccation-sensitive relatives but did not find significant difference in the NUMT/NUPT contents. Desiccation could induce DSBs, but it unlikely dramatically increase the frequency of foreign sequence integration in most eukaryotes. Only in the nuclear genomes enriched in repetitive sequences, the DSBs are predominantly repaired by non-homologous end joining (NHEJ) and desiccation-induced DSBs is possible to enhance the integration of foreign sequences into nuclear genome for some degree.

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How cells ensure correct repair of DNA double-strand breaks

Cited by 240 publications

References 98 publications

Replicated chromatin curtails 53BP1 recruitment in BRCA1-proficient and -deficient cells

Replicated chromatin curtails 53BP1 recruitment in BRCA1-proficient and -deficient cells

CNCC: An analysis tool to determine genome-wide DNA break end structure at single-nucleotide resolution

Desiccation Does Not Drastically Increase the Accessibility of Foreign DNA to the Nuclear Genomes: Evidence from the Frequency of Endosymbiotic DNA Transfer

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