Dynamics of double strand breaks and chromosomal translocations

Iarovaia, Olga V.; Rubtsov, Mikhail A.; Ioudinkova, E. S.; Tsfasman, Tatiana; Razin, Sergey V.; Vassetzky, Yegor S.

doi:10.1186/1476-4598-13-249

Cited by 44 publications

(43 citation statements)

References 101 publications

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“…Тhe CA model does not take into account the dynamics of DSBs or damaged chromosome subunits as only contact-first type mechanism is considered. Such dynamics can contribute to translocation yield [26] at different times after irradiation and may change the form of doseresponse curves. At genomic distances about 10 Mbp from I-SceI site (bait) CA frequencies deviate from those predicted from chromosomal contacts.…”

Section: Discussionmentioning

confidence: 99%

Spatial organization of the mouse chromosomes influences the landscape of intrachromosomal exchange aberration breakpoints

Eidelman

Salnikov

Slanina

et al. 2019

Preprint

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How 3D chromosome organization affects chromosomal aberrations is an important unresolved question in cell and radiation biology. In interphase the chromosomes form territories where chromatin folds into quite heterogeneous states. The mechanisms determining the spectrum of chromosome conformations remain poorly understood. We introduced the polymer model of mouse chromosome and generated the ensemble of 3D conformations. The chromosome model was validated against independent Hi-C (high-throughput chromosome conformation capture) data. The model described well Hi-C contact heatmap for chromosome 18 in pro-B mouse cells, both ATM-deficient and wild-type. We used the chromosome model to assess the role of chromosome structure in breakpoint distribution for intrachromosomal exchange aberrations. We investigated the effect of elevated frequency of breakpoints outside of the region of enzymatic breaksite. Chromosome aberration model explained breakpoint distribution under recurrent and ionizing radiation-induced DNA double-strand breaks in mouse chromosome 18 on the basis of contact-first mechanism. Overall, our results provide a framework for assessment of role of chromosome 3D organization on chromosome aberrations following DNA damage of different origin.

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Section: Discussionmentioning

confidence: 99%

Spatial organization of the mouse chromosomes influences the landscape of intrachromosomal exchange aberration breakpoints

Eidelman

Salnikov

Slanina

et al. 2019

Preprint

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“…DSBs are the most serious form of DNA damage because they pose subsequent problems for transcription, DNA replication, and chromosome segregation and are frequently associated with cellular transformation [81,82]. DSBs generated during DNA replication are normally repaired by the homologous recombination (HR) repair pathway [83], which is restricted to S/G2 phases of the cell cycle.…”

Section: Alteration Of Double-strand Breaks (Dsbs) By Taxmentioning

confidence: 99%

HTLV-I Tax-Mediated Inactivation of Cell Cycle Checkpoints and DNA Repair Pathways Contribute to Cellular Transformation: “A Random Mutagenesis Model”

Nicot

2015

J Cancer Sci

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To achieve cellular transformation, most oncogenic retroviruses use transduction by proto-oncogene capture or insertional mutagenesis, whereby provirus integration disrupts expression of tumor suppressors or proto-oncogenes. In contrast, the Human T-cell leukemia virus type 1 (HTLV-I) has been classified in a separate class referred to as “transactivating retroviruses”. Current views suggest that the viral encoded Tax protein transactivates expression of cellular genes leading to deregulated growth and transformation. However, if Tax-mediated transactivation was indeed sufficient for cellular transformation, a fairly high frequency of infected cells would eventually become transformed. In contrast, the frequency of transformation by HTLV-I is very low, likely less than 5%. This review will discuss the current understanding and recent discoveries highlighting critical functions of Tax in cellular transformation. HTLV-I Tax carries out essential functions in order to override cell cycle checkpoints and deregulate cellular division. In addition, Tax expression is associated with increased DNA damage and genome instability. Since Tax can inhibit multiple DNA repair pathways and stimulate unfaithful DNA repair or bypass checkpoints, these processes allow accumulation of genetic mutations in the host genome. Given this, a “Random Mutagenesis” transformation model seems more suitable to characterize the oncogenic activities of HTLV-I.

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“…If the repair of SSBs is deficient or disabled, SSBs can be converted to double‐strand breaks (DSBs) due to collapse or blockage of DNA replication forks during the S‐phase of the cell cycle . In this situation, the mechanisms of DSB repair will be activated and attempt to repair the lesion . Cells have developed sophisticated mechanisms with which to repair DSBs to maintain genetic fidelity because unrepaired or misrepaired DSBs can result in senescence, genetic instability, apoptosis, and transformation .…”

Section: Introductionmentioning

confidence: 99%

The emerging role of homologous recombination repair and PARP inhibitors in genitourinary malignancies

Rimar

Tran

Matulewicz

et al. 2017

Cancer

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As cells age and are exposed to genotoxic stress, preservation of the genomic code requires multiple DNA repair pathways to remove single or double- strand breaks. Loss of function somatic genomic aberrations or germline deficiency in genes involved in DNA repair can result in acute cell death or following a latency period cellular transformation. Therapeutic exploitation of DNA repair by inhibition of poly (adenosine diphosphate [ADP]) ribose polymerases (PARP), a family of enzymes involved in the repair of single-strand and in some cases double-strand breaks, has become a novel cancer treatment. While the application of PARP inhibitors (PARPis) was initially focused on tumors with BRCA1 or BRCA2 deficiency, our current knowledge has extended synthetic susceptibilities of PARPi to deficiencies in proteins and pathways involved in DNA damage repair (DDR) in particular those that repair double-strand breaks using homologous recombination (HR). There is an increasing appreciation that genitourinary (GU) malignancies, including bladder, and especially prostate cancers, contain subsets of patients with germline and somatic alterations in HR genes that may reflect increased response to PARPis. In this review, we describe the mechanisms and rationale of PARPi use in GU cancers, summarize previously reported pre-clinical and clinical trials, and identify ongoing trials to determine how PARPis and strategies targeted at HR repair can be applied for widespread application in GU cancers.

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Dynamics of double strand breaks and chromosomal translocations

Cited by 44 publications

References 101 publications

Spatial organization of the mouse chromosomes influences the landscape of intrachromosomal exchange aberration breakpoints

Spatial organization of the mouse chromosomes influences the landscape of intrachromosomal exchange aberration breakpoints

HTLV-I Tax-Mediated Inactivation of Cell Cycle Checkpoints and DNA Repair Pathways Contribute to Cellular Transformation: “A Random Mutagenesis Model”

The emerging role of homologous recombination repair and PARP inhibitors in genitourinary malignancies

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