Maintaining genome stability at the replication fork

Branzei, Dana; Foiani, Marco

doi:10.1038/nrm2852

Cited by 712 publications

(749 citation statements)

References 153 publications

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“…Even in the absence of exogenously inflicted stress, DNA replication forks may encounter a large number of potentially damaging adducts or lesions in the template DNA in each cell cycle. Undetected or inappropriately repaired lesions can lead to irreversible changes to chromosome structure, which can promote genomic instability and potentially the development of cancer 1,2 . To ensure the fidelity of DNA replication, cellular mechanisms have evolved to detect any perturbation of replication fork progress, and ensure that replication errors are corrected before cell division occurs.…”

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confidence: 99%

“…To ensure the fidelity of DNA replication, cellular mechanisms have evolved to detect any perturbation of replication fork progress, and ensure that replication errors are corrected before cell division occurs. If the lesions cannot be corrected in a timely fashion, cells are eliminated through cell death pathways [1][2][3] .…”

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confidence: 99%

“…Replication perturbation can lead to fork stalling, and in case of widespread stalling of replication forks cells enter a state commonly referred to as 'replicative stress' 1 . If these stressactivating obstacles are not removed or circumvented, forks can collapse, a poorly understood process where the replication machinery dissociates from the DNA and DNA double-strand breaks (DSBs) are subsequently generated 1 .…”

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confidence: 99%

“…If these stressactivating obstacles are not removed or circumvented, forks can collapse, a poorly understood process where the replication machinery dissociates from the DNA and DNA double-strand breaks (DSBs) are subsequently generated 1 .…”

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confidence: 99%

“…Cells experiencing replication stress activate checkpoint pathways, which in budding yeast have been shown to stabilize stalled replication forks 1,5 . In general, much less is known about the processing of stalled replication forks in mammalian cells.…”

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FBH1 co-operates with MUS81 in inducing DNA double-strand breaks and cell death following replication stress

et al. 2013

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The molecular events occurring following the disruption of DNA replication forks are poorly characterized, despite extensive use of replication inhibitors such as hydroxyurea in the treatment of malignancies. Here, we identify a key role for the FBH1 helicase in mediating DNA double-strand break formation following replication inhibition. We show that FBH1-deficient cells are resistant to killing by hydroxyurea, and exhibit impaired activation of the pro-apoptotic factor p53, consistent with decreased DNA double-strand break formation. Similar findings were obtained in murine ES cells carrying disrupted alleles of Fbh1. We also show that FBH1 through its helicase activity co-operates with the MUS81 nuclease in promoting the endonucleolytic DNA cleavage following prolonged replication stress. Accordingly, MUS81 and EME1-depleted cells show increased resistance to the cytotoxic effects of replication stress. Our data suggest that FBH1 helicase activity is required to eliminate cells with excessive replication stress through the generation of MUS81-induced DNA doublestrand breaks.

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FBH1 co-operates with MUS81 in inducing DNA double-strand breaks and cell death following replication stress

et al. 2013

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Moonlighting at replication forks – a new life for homologous recombination proteins BRCA1, BRCA2 and RAD51

et al. 2017

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Edited by Wilhelm JustCoordination between DNA replication and DNA repair ensures maintenance of genome integrity, which is lost in cancer cells. Emerging evidence has linked homologous recombination (HR) proteins RAD51, BRCA1 and BRCA2 to the stability of nascent DNA. This function appears to be distinct from double-strand break (DSB) repair and is in part due to the prevention of MRE11-mediated degradation of nascent DNA at stalled forks. The role of RAD51 in fork protection resembles the activity described for its prokaryotic orthologue RecA, which prevents nuclease-mediated degradation of DNA and promotes replication fork restart in cells challenged by DNA-damaging agents. Here, we examine the mechanistic aspects of HR-mediated fork protection, addressing the crosstalk between HR and replication proteins.Keywords: DNA recombination; DNA replication; genome stability BRCA1, BRCA2, RAD51 and the RAD51 paralogs family, which consists of five proteins (RAD51B, RAD51C, RAD51D, XRCC2 and XRCC3) in mammalian cells, are required to repair DNA damage by homologous recombination (HR). Mutations in most of these genes predispose to cancer, indicating an important role of DNA damage repair in preventing cell transformation. Intriguingly, complete loss of function of most of HR proteins is incompatible with life in vertebrate organisms [1,2,3]. These features together with their ability to form foci in unperturbed and challenged S-phase nuclei indicate a role for HR proteins in chromosomal DNA replication even in unchallenged conditions [4,5].The mechanisms underlying the function of DNA repair proteins in unchallenged chromosomal DNA replication are poorly understood. This is in part due to the fact that many of the genes involved in DNA metabolism are essential for cell viability, which complicate their study, especially in higher eukaryotes [1,2,3]. The reasons why HR genes are essential for cell viability in higher eukaryotes are unclear. One explanation might be that they have a specific and direct role in the replication of complex eukaryotic genomes. Alternatively, complex genomes might be more vulnerable to spontaneous DNA damage, which might irreversibly halt replication progression inducing chromosomes breakage. HR factors might be therefore required to repair the damage and to complete whole genome duplication. Here we review the links between HR proteins and the DNA replication machinery, some of which appear to be conserved between prokaryotes and eukaryotes.

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LIM protein Ajuba promotes liver cell proliferation through its involvement in DNA replication and DNA damage control

Stroka

2022

FEBS Letters

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The LIM-domain protein Ajuba is associated with cell proliferation, a fundamental process of tissue regeneration and cancer. We report that in the liver, Ajuba expression is increased during regeneration and in tumour cells and tissues. Knockout of Ajuba using CRISPR/Cas9 is embryonic lethal in mice. shRNA targeting of Ajuba reduces cell proliferation, delays cell entry into Sphase, reduces cell survival and tumour growth in vivo and increases expression of the DNA damage marker γH2AX. Ajuba binding partners include proteins involved in DNA replication and damage, such as SKP2, MCM2, MCM7 and RPA70. Taken together, our data support that Ajuba promotes liver cell proliferation associated with development, regeneration and tumour growth and is involved in DNA replication and damage repair.

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Maintaining genome stability at the replication fork

Cited by 712 publications

References 153 publications

FBH1 co-operates with MUS81 in inducing DNA double-strand breaks and cell death following replication stress

FBH1 co-operates with MUS81 in inducing DNA double-strand breaks and cell death following replication stress

Moonlighting at replication forks – a new life for homologous recombination proteins BRCA1, BRCA2 and RAD51

LIM protein Ajuba promotes liver cell proliferation through its involvement in DNA replication and DNA damage control

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