The "enemies within": regions of the genome that are inherently difficult to replicate

Bhowmick, Rahul; Hickson, Ian D.

doi:10.12688/f1000research.11024.1

Cited by 29 publications

(22 citation statements)

References 56 publications

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“…The effect is exacerbated when DNA replication is challenged by treating cells with low-dose aphidicolin (Aph, Figure 7C). Similar observations have been reported upon other genetic perturbations increasing endogenous replication stress and bona fide reflect genomic regions where replication is not complete upon entry into mitosis (Bhowmick and Hickson, 2017).…”

Section: Rnf168-deficient Cells Show Defects In Replicating Repetitivsupporting

confidence: 83%

Histone Ubiquitination by the DNA Damage Response Is Required for Efficient DNA Replication in Unperturbed S Phase

et al. 2018

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Chromatin ubiquitination by the ubiquitin ligase RNF168 is critical to regulate the DNA damage response (DDR). DDR deficiencies lead to cancer-prone syndromes, but whether this reflects DNA repair defects is still elusive. We identified key factors of the RNF168 pathway as essential mediators of efficient DNA replication in unperturbed S phase. We found that loss of RNF168 leads to reduced replication fork progression and to reversed fork accumulation, particularly evident at repetitive sequences stalling replication. Slow fork progression depends on MRE11-dependent degradation of reversed forks, implicating RNF168 in reversed fork protection and restart. Consistent with regular nucleosomal organization of reversed forks, the replication function of RNF168 requires H2A ubiquitination. As this novel function is shared with the key DDR players ATM, γH2A.X, RNF8, and 53BP1, we propose that double-stranded ends at reversed forks engage classical DDR factors, suggesting an alternative function of this pathway in preventing genome instability and human disease.

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Section: Rnf168-deficient Cells Show Defects In Replicating Repetitivsupporting

confidence: 83%

Histone Ubiquitination by the DNA Damage Response Is Required for Efficient DNA Replication in Unperturbed S Phase

et al. 2018

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“…Although there is a low frequency of complex rearrangement initially associated with chromosome bridges in the first interphase after the bridge has formed, we hypothesized that additional DNA damage might arise downstream of bridge breakage. First, chromosome bridges contain segments of incomplete DNA replication and probably stalled replication forks that could undergo replication fork breakage upon entry into mitosis (51, 52). Second, we found that complex rearrangements were frequent in the second generation (i.e.…”

Section: Resultsmentioning

confidence: 99%

Mechanisms Generating Cancer Genome Complexity From A Single Cell Division Error

Umbreit

Chen

Lynch

et al. 2019

Preprint

154

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ABSTRACTThe chromosome breakage-fusion-bridge (BFB) cycle is a mutational process that produces gene amplification and genome instability. Signatures of BFB cycles can be observed in cancer genomes with chromothripsis, another catastrophic mutational process. Here, we explain this association by identifying a mutational cascade downstream of chromosome bridge formation that generates increasing amounts of chromothripsis. We uncover a new role for actomyosin forces in bridge breakage and mutagenesis. Chromothripsis then accumulates starting with aberrant interphase replication of bridge DNA, followed by an unexpected burst of mitotic DNA replication, generating extensive DNA damage. Bridge formation also disrupts the centromeric epigenetic mark, leading to micronucleus formation that itself promotes chromothripsis. We show that this mutational cascade generates the continuing evolution and sub-clonal heterogeneity characteristic of many human cancers.

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“…In this scenario, one intact daughter chromosome is immediately restored by gap filling, and the other is regenerated via joining of the two broken ends, albeit with sister chromatid exchange and at the cost of of a small deletion (Figure S7, left branch). Importantly, this mechanism avoids the formation of acentric and dicentric chromosomes that would result from random breakage of the forks (Figure S7, right branch) and thus helps account for the fact that breakage at CFS is mostly beneficial (Bhowmick and Hickson, 2017; Minocherhomji et al, 2015; Naim et al, 2013; Ying et al, 2013). Strikingly, CFS expression induces chromosomal alterations that exhibit key features expected of our model, including submicroscopic deletions covering the CFS locus, microhomologies at the breakpoint junctions, and a very high frequency of sister chromatid exchanges (Glover et al, 2017) (Figure S7, left branch).…”

Section: Discussionmentioning

confidence: 99%

Mitotic CDK promotes replisome disassembly, fork breakage, and complex DNA rearrangements

Deng

Kochenova

et al. 2018

Preprint

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22DNA replication errors generate complex chromosomal rearrangements and thereby 23 contribute to tumorigenesis and other human diseases. Although the events that trigger 24 these errors are not well understood, one candidate is mitotic entry before the 25 completion of DNA replication. To address the impact of mitosis on DNA replication, we 26 employed Xenopus egg extracts. When mitotic CDK (Cyclin B1-CDK1) is used to drive 27 these extracts into mitosis, the E3 ubiquitin ligase TRAIP promotes ubiquitylation of the 28 replicative CMG (CDC45/MCM2-7/GINS) helicase at stalled forks and at forks that have 29 completed DNA synthesis. In both cases, ubiquitylation is followed by CMG extraction 30 from chromatin by the CDC48/p97 ATPase. At stalled forks, CMG removal results in 31 fork breakage and complex end joining events involving deletions and template-32 switching. Our results identify TRAIP-dependent replisome disassembly as a novel 33 trigger of replication fork collapse and propose it underlies complex DNA 34 rearrangements in mitosis. 35 3 HIGHLIGHTS 36 1. TRAIP-dependent MCM7 ubiquitylation removes all CMGs from chromatin in 37 mitosis 38 2. CMG unloading from stalled forks causes replication fork breakage 39 3. Replication fork breakage in mitosis causes complex rearrangements 40 4. New model of replication fork collapse 41 42 43Genome evolution occurs through the gradual accrual of genetic changes or in a 44 saltatory manner, with bursts of chromosomal alterations originating from single 45 catastrophic events (Holland and Cleveland, 2012; Leibowitz et al., 2015; Liu et al., 46 2011; Stephens et al., 2011). Many chromosomal alterations can be traced to DNA 47 breaks that arise during DNA replication (Hills and Diffley, 2014; Mankouri et al., 2013; 48 Techer et al., 2017). However, there is an ongoing debate about when and how 49 replication fork breakage is triggered (Toledo et al., 2017). 50In normal cells, multiple cell cycle regulatory controls and error correction 51 mechanisms prevent DNA replication errors (Hills and Diffley, 2014). Cells prepare for 52 DNA replication in the G1 phase of the cell cycle, when pairs of MCM2-7 ATPases are 53 recruited to each origin ("licensing"). In S phase, cyclin-dependent kinase (CDK) 54 promotes the association of CDC45 and GINS with MCM2-7, leading to formation of the 55 replicative CMG helicase complex (CDC45-MCM2-7-GINS) ("initiation"). CMG 56 unwinding of the origin nucleates the assembly of two DNA replication forks that travel 57 away from the origin, copying DNA as they go ("elongation"). When converging forks 58 from adjacent origins meet, the replisome is disassembled ("termination"). Replisome 59 disassembly in S phase requires the E3 ubiquitin ligase CRL2 Lrr1 , which ubiquitylates 60 the MCM7 subunit of CMG, leading to CMG's extraction from chromatin by the p97 61 ATPase (Dewar et al., 2017; Sonneville et al., 2017). In the absence of CRL2 Lrr1 , CMGs 62 persist on chromatin until mitosis, but are then removed by a secondary, p97-dependent ...

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The "enemies within": regions of the genome that are inherently difficult to replicate

Cited by 29 publications

References 56 publications

Histone Ubiquitination by the DNA Damage Response Is Required for Efficient DNA Replication in Unperturbed S Phase

Histone Ubiquitination by the DNA Damage Response Is Required for Efficient DNA Replication in Unperturbed S Phase

Mechanisms Generating Cancer Genome Complexity From A Single Cell Division Error

Mitotic CDK promotes replisome disassembly, fork breakage, and complex DNA rearrangements

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