Fanconi anemia proteins and genome fragility: unraveling replication defects for cancer therapy

Fajardo, Nibal Badra; Taraviras, Stavros; Lygerou, Zoi

doi:10.1016/j.trecan.2022.01.015

Cited by 17 publications

(14 citation statements)

References 146 publications

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“…MUS81, SLX4, and FANCQ cleave the crosslinked DNA via unhooking. The crosslinked nucleotide base paired to the complementary DNA and the lesion is bypassed via translesion synthesis [ 91 , 92 , 93 ]. FANCD2-I proteins are then deubiquitinated by the USP1-UAF1 complex [ 91 , 92 , 93 , 94 , 95 , 96 ].…”

Section: The Different Dna Damage Repair Pathways and Their Associati...mentioning

confidence: 99%

“…The crosslinked nucleotide base paired to the complementary DNA and the lesion is bypassed via translesion synthesis [ 91 , 92 , 93 ]. FANCD2-I proteins are then deubiquitinated by the USP1-UAF1 complex [ 91 , 92 , 93 , 94 , 95 , 96 ]. Mutations in the FA pathway proteins lead to Fanconi anemia , associated with leukemias, ovarian, breast and other cancers [ 92 ].…”

Section: The Different Dna Damage Repair Pathways and Their Associati...mentioning

confidence: 99%

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Interplay between the DNA Damage Response and Immunotherapy Response in Cancer

Lee

Kok

Teh

et al. 2022

IJMS

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Genome instability and immune evasion are both defining hallmarks of cancer. Tumorigenesis is frequently initiated when there is DNA damage to a proto-oncogene or tumor suppressor gene and DNA repair mechanisms are lost or insufficient to correct the damage; immune evasion then prevents the host immune system from recognizing these transformed cells. Therapies targeting genomic instability and immune evasion have been effectively used to treat cancer. Genotoxic therapies such as chemoradiation have been employed in cancer treatments for several decades, while immunotherapy is a relatively new class of cancer therapy that has led to disease regression even in patients with advanced cancer. Several recent studies have shown synergy between both classes of therapy targeting these two defining hallmarks of cancer, and different mechanisms are proposed to be involved. Here, we review the different classes of DNA damage, their links to cancer, and their contribution to immunotherapy responses, as well as the different models that are currently being used to study tumor–immune interactions.

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Section: The Different Dna Damage Repair Pathways and Their Associati...mentioning

confidence: 99%

Section: The Different Dna Damage Repair Pathways and Their Associati...mentioning

confidence: 99%

Interplay between the DNA Damage Response and Immunotherapy Response in Cancer

Lee

Kok

Teh

et al. 2022

IJMS

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“…To date, variants in more than 20 genes (FANCA to FANCW) have been found to cause FA as an autosomal recessive (AR) trait, in FANCB exhibits X-linked (XL) inheritance, and in FANCR/RAD51, which have been associated with an autosomal dominant (AD) rare disease trait (Ameziane et al 2015;Badra Fajardo et al 2022;Moreno et al 2021;Wang et al 2015). All proteins form an integrated protein network, known as the FA/BRCA repair pathway (Ceccaldi et al 2016).…”

Section: Introductionmentioning

confidence: 99%

“…The network is active during DNA replication when converging replisomes encounter damage that covalently binds the two DNA strands (interstrand crosslinking; ICL). Sequential recruitment of FA proteins and associated partners onto chromatin unhooks the ICL and coordinates the repair through homologous monoubiquitination and recombination (Badra Fajardo et al 2022;Moreno et al 2021;Nalepa and Clapp 2018). Emerging evidence suggests that independent of ICL and homologous recombination (HR) repair, FA proteins also regulate cell-cycle checkpoints and/or promote replication fork remodeling in response to replication stress, redefining the FA pathway as a cardinal mechanism to preserve genome integrity throughout the entire replication process (Badra Fajardo et al 2022).…”

Section: Introductionmentioning

confidence: 99%

“…Alterations in FA genes have been found to incite genomic instability and contribute to tumorigenesis (Badra Fajardo et al 2022). Accordingly, cells from FA patients are hypersensitive to ICL-inducing agents such as diepoxybutane (DEB) and mitomycin C (MMC), which cause high levels of chromosomal aberrations, including chromosomal breaks and quadriradial formation.…”

Section: Introductionmentioning

confidence: 99%

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SNV/indel hypermutator phenotype in biallelic RAD51C variant: Fanconi anemia

Zemet

Gambin

et al. 2023

Hum Genet

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We previously reported a fetus with Fanconi anemia (FA), complementation group O due to compound heterozygous variants involving RAD51C. Interestingly, the trio exome sequencing analysis also detected eight apparent de novo mosaic variants with variant allele fraction (VAF) ranging between 11.5%-37%. Here, using whole genome sequencing and a 'home-brew' variant filtering pipeline and DeepMosaic module, we investigated the number and signature of de novo heterozygous and mosaic variants and the rare phenomenon of hypermutation. Eight-hundred-thirty apparent dnSNVs and 21 de novo indels had VAFs below 37.41% and were considered postzygotic somatic mosaic variants.The VAFs showed a bimodal distribution, with one component with an average VAF of 25% (range: 18.7-37.41%) (n=446), representing potential postzygotic first mitotic events, and the other component with an average VAF of 12.5% (range: 9.55-18.69%) (n=384), describing potential second mitotic events. No increased rate of CNV formation was observed. The mutational pattern analysis for somatic single base substitution showed SBS40, SBS5, and SBS3 as the top recognized signatures. SBS3 is a known signature associated with homologous recombination-based DNA damage repair error. Our data demonstrate that biallelic RAD51C variants show evidence for defective genomic DNA damage repair and thereby result in a hypermutator phenotype with the accumulation of postzygotic de novo mutations, at least in the prenatal period. This 'genome hypermutator phenomenon' might contribute to the observed hematological manifestations and the predisposition to tumors in patients with FA, and pregnancy loss in general. We propose that other FA groups should be investigated for genome-wide de novo variants.

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The Compromised Fanconi Anemia Pathway in Prelamin A‐Expressing Cells Contributes to Replication Stress‐Induced Genomic Instability

Nie,

Zhang,

et al. 2024

Advanced Science

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Genomic instability is not only a hallmark of senescent cells but also a key factor driving cellular senescence, and replication stress is the main source of genomic instability. Defective prelamin A processing caused by lamin A/C (LMNA) or zinc metallopeptidase STE24 (ZMPSTE24) gene mutations results in premature aging. Although previous studies have shown that dysregulated lamin A interferes with DNA replication and causes replication stress, the relationship between lamin A dysfunction and replication stress remains largely unknown. Here, an increase in baseline replication stress and genomic instability is found in prelamin A‐expressing cells. Moreover, prelamin A confers hypersensitivity of cells to exogenous replication stress, resulting in decreased cell survival and exacerbated genomic instability. These effects occur because prelamin A promotes MRE11‐mediated resection of stalled replication forks. Fanconi anemia (FA) proteins, which play important roles in replication fork maintenance, are downregulated by prelamin A in a retinoblastoma (RB)/E2F‐dependent manner. Additionally, prelamin A inhibits the activation of the FA pathway upon replication stress. More importantly, FA pathway downregulation is an upstream event of p53‐p21 axis activation during the induction of prelamin A expression. Overall, these findings highlight the critical role of FA pathway dysfunction in driving replication stress‐induced genomic instability and cellular senescence in prelamin A‐expressing cells.

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Fanconi anemia proteins and genome fragility: unraveling replication defects for cancer therapy

Cited by 17 publications

References 146 publications

Interplay between the DNA Damage Response and Immunotherapy Response in Cancer

Interplay between the DNA Damage Response and Immunotherapy Response in Cancer

SNV/indel hypermutator phenotype in biallelic RAD51C variant: Fanconi anemia

The Compromised Fanconi Anemia Pathway in Prelamin A‐Expressing Cells Contributes to Replication Stress‐Induced Genomic Instability

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