RAD51 protects human cells from transcription-replication conflicts

Bhowmick, Rahul; Lerdrup, Mads; Gadi, Sampath Amitash; Rossetti, Giacomo G.; Singh, Manika; Liu, Ying; Halazonetis, Thanos D.; Hickson, Ian

doi:10.1016/j.molcel.2022.07.010

Cited by 25 publications

(15 citation statements)

References 82 publications

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“…RAD52 is a protein involved in BIR in the nucleus. In human cells defective for RAD52, BIR was found to re-replicate an affected segment of the genome [48]. The product of such re-replication is tandem copies in potentially great numbers found in centromeres, sub-telomeres, or any part of a genome.…”

Section: Resultsmentioning

confidence: 99%

Ribosomal intergenic spacers are filled with transposon remnants

Bendich

Rogers

2023

Preprint

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Eukaryotic ribosomal DNA (rDNA) comprises tandem units of highly-conserved coding genes separated by rapidly-evolving spacer DNA. The spacers of all 12 species examined were filled with short direct repeats (DRs) and multiple long tandem repeats (TRs), completing the rDNA maps that previously contained unannotated and inadequately studied sequences. The external transcribed spacers also were filled with DRs and some contained TRs. We infer that the spacers arose from transposon insertion, followed by their imprecise excision, leaving short DRs characteristic of transposon visitation. The spacers provided a favored location for transposon insertion because they occupy loci containing hundreds to thousands of gene repeats. The spacers' primary cellular function may be to link one rRNA transcription unit to the next, whereas transposons flourish here because they have colonized the most frequently-used part of the genome.

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Section: Resultsmentioning

confidence: 99%

Ribosomal intergenic spacers are filled with transposon remnants

Bendich

Rogers

2023

Preprint

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“…As shown in figures 2C and 2D, the expression of the inactive FLAG-SET8 PIPmut+SETmut , but not of FLAG-SET8 PIPmut , failed to reduce RAD51 foci formation and to stimulate 53BP1 focal accumulation during S-phase. Noted of, defects in RAD51 foci formation during DNA replication are sufficient to impair homologous recombination (HR) and trigger genome instability (Bhowmick et al 2022, 51; Costanzo et al 2011; Feu et al 2022). Consistent with this, we noticed at late time points the appearance of γH2A.X foci that mostly coincided with the presence of 53BP1 foci in FLAG-SET8 PIPmut cells (Figures S1C and S1D).…”

Section: Resultsmentioning

confidence: 99%

Cell-cycle dependent inhibition of BRCA1 signaling by the lysine methyltransferase SET8

Perez,

Alhourani,

Patouillard

et al. 2023

Preprint

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SUMMARYAlthough the inverse affinities of 53BP1 and BRCA1-BARD1 complexes for distinct methylation states of lysine (K) 20 at histone H4 have underscored a role of this epigenetic mark in the regulation of DNA-repair pathways choice, how the different H4K20 methyltransferases are involved remained unclear. Here, we show that the replication-coupled degradation of the lysine methyltransferase SET8 responsible for H4K20 mono-methylation (H4K20me1) is required for the onset of the recombinogenic functions of BRCA1 during unperturbed DNA replication. Indeed, we demonstrate that SET8 can work as a primary inhibitor of homologous recombination by tipping the balance from BRCA1-BARD1 to 53BP1 complexes in a manner depending on the single switch from un-methyl to mono-methyl H4K20 and the recruitment of the ubiquitin ligase RNF168 on post-replicated chromatin. Conversely, the lack of SET8 and K20 mono-methylation on newly assembly chromatin after DNA replication led to the untimely chromatin accumulation of BRCA1 at the exit of mitosis, which contributes to the improper progression from G1 to S-phase in daughter cells. Altogether, these results establish thede novoactivity of SET8 on chromatin as a primordial epigenetic lock of BRCA1-mediated HR pathway during the cell cycle.

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“…It will be important in the future to understand how FANCD2 functionally interacts with SLX4, and with the other members of the FA pathway, to promote SSE-mediated resolution of these structures. Finally, the synthetic proliferation defect and the difference in the impact of SETX depletion in cancerous versus the noncancerous cell lines hint towards therapeutic strategies targeting endogenous RS in tumors, especially in specific genetic backgrounds [71][72][73] or contexts characterized by increased TRCs, such as following oncogene activation, metabolic stress or estrogenstimulated transcription [74][75][76] . For example, even if germline mutations in SETX associated with neurodegenerative disorders do not reportedly increase cancer risk, SETX somatic mutations and CNVs are commonly found in tumors, particularly in gynecological and colon cancers (data from The Cancer Genome Atlas (TGCA) Program) 77 .…”

Section: Discussionmentioning

confidence: 99%

FANCD2 promotes mitotic rescue from transcription-mediated replication stress in SETX-deficient cancer cells

et al. 2022

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Replication stress (RS) is a leading cause of genome instability and cancer development. A substantial source of endogenous RS originates from the encounter between the transcription and replication machineries operating on the same DNA template. This occurs predominantly under specific contexts, such as oncogene activation, metabolic stress, or a deficiency in proteins that specifically act to prevent or resolve those transcription-replication conflicts (TRCs). One such protein is Senataxin (SETX), an RNA:DNA helicase involved in resolution of TRCs and R-loops. Here we identify a synthetic lethal interaction between SETX and proteins of the Fanconi anemia (FA) pathway. Depletion of SETX induces spontaneous under-replication and chromosome fragility due to active transcription and R-loops that persist in mitosis. These fragile loci are targeted by the Fanconi anemia protein, FANCD2, to facilitate the resolution of under-replicated DNA, thus preventing chromosome mis-segregation and allowing cells to proliferate. Mechanistically, we show that FANCD2 promotes mitotic DNA synthesis that is dependent on XPF and MUS81 endonucleases. Importantly, co-depleting FANCD2 together with SETX impairs cancer cell proliferation, without significantly affecting non-cancerous cells. Therefore, we uncovered a synthetic lethality between SETX and FA proteins for tolerance of transcription-mediated RS that may be exploited for cancer therapy.

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RAD51 protects human cells from transcription-replication conflicts

Cited by 25 publications

References 82 publications

Ribosomal intergenic spacers are filled with transposon remnants

Ribosomal intergenic spacers are filled with transposon remnants

Cell-cycle dependent inhibition of BRCA1 signaling by the lysine methyltransferase SET8

FANCD2 promotes mitotic rescue from transcription-mediated replication stress in SETX-deficient cancer cells

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