FANCJ is essential to maintain microsatellite structure genome-wide during replication stress

Barthelemy, Joanna; Leffak, Michael

doi:10.1093/nar/gkw1091

Cited by 24 publications

(3 citation statements)

References 74 publications

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“…The human RTEL helicase can unwind CAG and CTG hairpins in vitro, substitute for yeast Srs2 in protecting against fragility, and prevent CAG expansions in a human cell system . The Sgs1 homolog WRN was also found to unwind CAG/CTG repeat hairpins and prevent repeat contractions, and the FANCJ helicase suppresses microsatellite and CAG/CTG repeat instability . Thus, multiple helicases likely cooperate to unwind hairpin structures and prevent repeat instability and chromosome fragility.…”

Section: Types Of Secondary Structures and Links To Fork Stalling Andmentioning

confidence: 99%

The role of fork stalling and DNA structures in causing chromosome fragility

Kaushal

Freudenreich

2019

Genes Chromosomes & Cancer

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Alternative non‐B form DNA structures, also called secondary structures, can form in certain DNA sequences under conditions that produce single‐stranded DNA, such as during replication, transcription, and repair. Direct links between secondary structure formation, replication fork stalling, and genomic instability have been found for many repeated DNA sequences that cause disease when they expand. Common fragile sites (CFSs) are known to be AT‐rich and break under replication stress, yet the molecular basis for their fragility is still being investigated. Over the past several years, new evidence has linked both the formation of secondary structures and transcription to fork stalling and fragility of CFSs. How these two events may synergize to cause fragility and the role of nuclease cleavage at secondary structures in rare and CFSs are discussed here. We also highlight evidence for a new hypothesis that secondary structures at CFSs not only initiate fragility but also inhibit healing, resulting in their characteristic appearance.

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Section: Types Of Secondary Structures and Links To Fork Stalling Andmentioning

confidence: 99%

The role of fork stalling and DNA structures in causing chromosome fragility

Kaushal

Freudenreich

2019

Genes Chromosomes & Cancer

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“…Flipping the coin, FANCJ may play a role in preventing fork stalling in the first place by resolving alternate DNA structures such as G-quadruplexes, as mentioned above. Recently, two laboratories independently showed that FANCJ prevents microsatellite instability during replication to suppress chromosome breakage and translocations, presumably by resolving non-B DNA structures in a manner that is independent of the classic FA pathway used to repair ICLs [ 166 , 167 ]. Thus, FANCJ operates at four distinct levels during replication stress or DNA repair to maintain genomic stability ( Figure 2 ).…”

Section: New Developments In Understanding Fancj’s Role In the Repmentioning

confidence: 99%

Holding All the Cards—How Fanconi Anemia Proteins Deal with Replication Stress and Preserve Genomic Stability

Datta

Brosh

2019

Genes

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Fanconi anemia (FA) is a hereditary chromosomal instability disorder often displaying congenital abnormalities and characterized by a predisposition to progressive bone marrow failure (BMF) and cancer. Over the last 25 years since the discovery of the first linkage of genetic mutations to FA, its molecular genetic landscape has expanded tremendously as it became apparent that FA is a disease characterized by a defect in a specific DNA repair pathway responsible for the correction of covalent cross-links between the two complementary strands of the DNA double helix. This pathway has become increasingly complex, with the discovery of now over 20 FA-linked genes implicated in interstrand cross-link (ICL) repair. Moreover, gene products known to be involved in double-strand break (DSB) repair, mismatch repair (MMR), and nucleotide excision repair (NER) play roles in the ICL response and repair of associated DNA damage. While ICL repair is predominantly coupled with DNA replication, it also can occur in non-replicating cells. DNA damage accumulation and hematopoietic stem cell failure are thought to contribute to the increased inflammation and oxidative stress prevalent in FA. Adding to its confounding nature, certain FA gene products are also engaged in the response to replication stress, caused endogenously or by agents other than ICL-inducing drugs. In this review, we discuss the mechanistic aspects of the FA pathway and the molecular defects leading to elevated replication stress believed to underlie the cellular phenotypes and clinical features of FA.

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“…This strongly suggests that defects in the FA pathway might increase the risk of developing HNSCCs. On a cellular level, defects in FA genes cause multiple defects including spontaneous genetic instability, hypersensitivity to DNA interstrand cross-linking agents, impaired selective autophagy, defective chromosome segregation and aneuploidy, hypersensitivities to oxidative stress and inflammatory cytokines as well as problems in telomere maintenance and replication (24)(25)(26)(27)(28)(29). All these cellular abnormalities promote malignant transformation of cells, thus explaining the high incidence of malignancies in FA patients.…”

mentioning

confidence: 99%

Mutational and Functional Analysis of FANCB as a Candidate Gene for Sporadic Head and Neck Squamous Cell Carcinomas

Glaas

Wiek

Wolter

et al. 2018

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Abstract. Background Head and neck squamous cell carcinomas (HNSCCs) are the 6th most common type of cancers worldwide with varying rates in different ethnic populations (1-4). In the USA alone, over 60,000 new cases of HNSCCs are diagnosed and more than 13,000 patients die from HNSCCs each year (5). The tumor cells originate from the epithelium of the upper aerodigestive tract and undergo malignant transformation in a multistep process that is strongly influenced by an interplay between extrinsic (e.g. environmental or behavioral) and intrinsic (predominantly genetic) factors (1, 6). The four major cellular pathways implicated in the pathogenesis of HNSCCs are proliferation/survival, cell-cycle control, differentiation and adhesion/invasion signaling (7). The dysregulation of these pathways in the malignant cells is caused by somatic alterations/mutations in key genes such as TP53, HRAS, CCND1, NOTCH1 and others (7-9).The major behavioral risk factors for the development of HNSCCs are increased consumption of tobacco, and alcohol, but also infection with oncogenic human papilloma virus (HPV) (1, 2, 7). Several research groups including ours have established that a minority of patients with heterozygous germline mutations in known cancer susceptibility genes has an increased risk to develop HNSCC even in the absence of other behavioral risk

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FANCJ is essential to maintain microsatellite structure genome-wide during replication stress

Cited by 24 publications

References 74 publications

The role of fork stalling and DNA structures in causing chromosome fragility

The role of fork stalling and DNA structures in causing chromosome fragility

Holding All the Cards—How Fanconi Anemia Proteins Deal with Replication Stress and Preserve Genomic Stability

Mutational and Functional Analysis of FANCB as a Candidate Gene for Sporadic Head and Neck Squamous Cell Carcinomas

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