Homologous recombination repair intermediates promote efficient de novo telomere addition at DNA double-strand breaks

Davé, Anoushka; Pai, Chen-Chun; Durley, Samuel C.; Hulme, Lydia; Sarkar, Sovan; Wee, Boon-Yu; Prudden, John; Tinline-Purvis, Helen; Cullen, Jason K.; Walker, Carol; Watson, Adam T.; Carr, Antony; Murray, Johanne M.; Humphrey, Timothy C.

doi:10.1093/nar/gkz1109

Cited by 11 publications

(14 citation statements)

References 71 publications

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“…Extensive LOH was significantly reduced in rqh1Δ exo1Δ Ch 16 -Tel-DSB cells, consistent with Ch I formation requiring extensive processing (11,12) ( Fig. 1D), with LOH resulting instead from de novo telomere addition (dnTA) (13).…”

supporting

confidence: 62%

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Persistent broken chromosome inheritance drives genome instability

Pai

Durley

Cheng

et al. 2020

Preprint

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Persistent DNA damage arising from unrepaired broken chromosomes or telomere loss can promote DNA damage checkpoint adaptation, and cell cycle progression, thereby increasing cell survival but also genome instability. However, the nature and extent of such instability is unclear. We show, using Schizosaccharomyces pombe, that inherited broken chromosomes, arising from failed homologous recombination repair, are subject to cycles of segregation, DNA replication and extensive end-processing, termed here SERPent cycles, by daughter cells, over multiple generations. Following Chk1 loss these post-adaptive cycles continue until extensive processing through inverted repeats promotes annealing, fold-back inversion and a spectrum of chromosomal rearrangements, typically isochromosomes, or chromosome loss, in the resultant population. These findings explain how persistent DNA damage drives widespread genome instability, with implications for punctuated evolution, genetic disease and tumorigenesis.One Sentence SummaryReplication and processing of inherited broken chromosomes drives chromosomal instability.

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supporting

confidence: 62%

“…S4, H and I).LOH9 exhibited a duplication of a larger portion the centromeric region, explaining the increased minichromosome size compared to LOH1(fig. S4I).In contrast, LOH5, was found to have retained some of the right arm, consistent with de novo telomere addition(13,21) (fig. S4J).…”

supporting

confidence: 52%

Persistent broken chromosome inheritance drives genome instability

Pai

Durley

Cheng

et al. 2020

Preprint

Self Cite

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“…This sequence can then be used as a template for largely accurate repair. Meanwhile, extended DNA end resection contributes to nonligatable DNA breaks and hampers end joining; consequently, DNA end resection is dominant [186][187][188] . Hence, HR is initiated only when a repair template exists, which can limit the potential for illegitimate recombination.…”

Section: Dna Dsb Repair Pathwaysmentioning

confidence: 99%

DNA damage response signaling pathways and targets for radiotherapy sensitization in cancer

Huang

Zhou

2020

Sig Transduct Target Ther

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Radiotherapy is one of the most common countermeasures for treating a wide range of tumors. However, the radioresistance of cancer cells is still a major limitation for radiotherapy applications. Efforts are continuously ongoing to explore sensitizing targets and develop radiosensitizers for improving the outcomes of radiotherapy. DNA double-strand breaks are the most lethal lesions induced by ionizing radiation and can trigger a series of cellular DNA damage responses (DDRs), including those helping cells recover from radiation injuries, such as the activation of DNA damage sensing and early transduction pathways, cell cycle arrest, and DNA repair. Obviously, these protective DDRs confer tumor radioresistance. Targeting DDR signaling pathways has become an attractive strategy for overcoming tumor radioresistance, and some important advances and breakthroughs have already been achieved in recent years. On the basis of comprehensively reviewing the DDR signal pathways, we provide an update on the novel and promising druggable targets emerging from DDR pathways that can be exploited for radiosensitization. We further discuss recent advances identified from preclinical studies, current clinical trials, and clinical application of chemical inhibitors targeting key DDR proteins, including DNA-PKcs (DNA-dependent protein kinase, catalytic subunit), ATM/ATR (ataxia-telangiectasia mutated and Rad3-related), the MRN (MRE11-RAD50-NBS1) complex, the PARP (poly[ADP-ribose] polymerase) family, MDC1, Wee1, LIG4 (ligase IV), CDK1, BRCA1 (BRCA1 C terminal), CHK1, and HIF-1 (hypoxia-inducible factor-1). Challenges for ionizing radiation-induced signal transduction and targeted therapy are also discussed based on recent achievements in the biological field of radiotherapy.

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“…It has been shown that truncation ends are healed by de novo telomere addition (Dave et al, 2020;Matsumoto et al, 1987;Pennaneach et al, 2006). To determine the chromosomal sites to which telomere sequences have been added, we amplified the breakpoints using a pair of ChL C and telomere primers: M13R-C19 or M13R-T1 (Irie et al, 2019) and chromosomal truncations recovered from agarose gels.…”

Section: Fission Yeast Rad8 Facilitates Isochromosome Formation But Nmentioning

confidence: 99%

Fission yeast Rad8/HLTF facilitates Rad52-dependent chromosomal rearrangements through PCNA lysine 107 ubiquitination

Nakagawa

Toyofuku

2021

Preprint

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Rad52 recombinase can cause gross chromosomal rearrangements (GCRs). However, the mechanism of Rad52-dependent GCRs remains unclear. Here, we show that fission yeast Rad8/HLTF facilitates Rad52-dependent GCRs through the ubiquitination of lysine 107 (K107) of PCNA, a DNA sliding clamp. Loss of Rad8 reduced isochromosomes resulting from centromere inverted repeat recombination. Rad8 HIRAN and RING finger mutations reduced GCRs, suggesting that Rad8 facilitates GCRs through 3’ DNA-end binding and ubiquitin ligase activity. Mms2 and Ubc4 but not Ubc13 ubiquitin-conjugating proteins were required for GCRs. Consistent with this, PCNA K107R but not K164R mutation greatly reduced GCRs. Rad8-dependent PCNA K107 ubiquitination facilitates Rad52-dependent GCRs, as PCNA K107R, rad8, and rad52 mutations epistatically reduced GCRs. Remarkably, K107 is located at the interface between PCNA subunits, and an interface mutation D150E bypassed the requirement of PCNA K107 ubiquitination for GCRs. This study uncovers the role of Rad8-dependent PCNA K107 ubiquitination in Rad52-dependent GCRs.

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Homologous recombination repair intermediates promote efficient de novo telomere addition at DNA double-strand breaks

Cited by 11 publications

References 71 publications

Persistent broken chromosome inheritance drives genome instability

Persistent broken chromosome inheritance drives genome instability

DNA damage response signaling pathways and targets for radiotherapy sensitization in cancer

Fission yeast Rad8/HLTF facilitates Rad52-dependent chromosomal rearrangements through PCNA lysine 107 ubiquitination

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