The Fanconi anaemia pathway orchestrates incisions at sites of crosslinked DNA

Crossan, Gerry P.; Patel, Ketan

doi:10.1002/path.3002

Cited by 99 publications

(99 citation statements)

References 151 publications

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“…5 FA can, therefore, be regarded as an inherited DNA repair disorder. Despite these advances, the precise pathophysiology of the bone marrow failure in FA has remained elusive.…”

mentioning

confidence: 99%

Heightened DNA damage response impairs hematopoiesis in Fanconi anemia

Dokal¹

2012

Haematologica

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“…5 FA can, therefore, be regarded as an inherited DNA repair disorder. Despite these advances, the precise pathophysiology of the bone marrow failure in FA has remained elusive.…”

mentioning

confidence: 99%

Heightened DNA damage response impairs hematopoiesis in Fanconi anemia

Dokal¹

2012

Haematologica

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“…This is followed by the removal of nonhomologous 3′ single-stranded flaps between the two repeats ( Figure 5), which is catalysed by a XPF-ERCC1 heterodimer that harbours 5′-3′ structure-specific endonuclease activity (134). In addition to SSA, XPF-ERCC1 also plays an important role in other DNA repair pathways including NER, FA and A-NHEJ (alternative-NHEJ; discussed below).…”

Section: The Ssa Sub-pathwaymentioning

confidence: 99%

“…Eight FA proteins (FANCA/B/C/E/F/G/L/M) form a multisubunit nuclear complex, known as the FA core complex, which through FANCL, acts as an ubiquitin E3 ligase to mono-ubiquitinate FANCD2 and FANCI following DNA damage [131,134,135].…”

Section: R3 Formation Of Fa Core Complexmentioning

confidence: 99%

“…This unhooking process converts a stalled replication fork into a DSB. FANCP and FAN1 may also contribute to this process [131,134,141].…”

Section: R11 Dual Incision On Each Side Of the Icl Performed By Mus81mentioning

confidence: 99%

“…It belongs to a family known as translesion synthesis polymerases which are low fidelity DNA polymerases that allow cells to replicate over the replication-blocking lesions without correcting it [131,134,142].…”

Section: R15 Formation Of the Dna Pol Zeta Complexmentioning

confidence: 99%

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Computational analysis of DNA repair pathways in breast cancer

Liu¹

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The integrity of the human genome is constantly challenged by a variety of endogenous and exogenous factors such as ultraviolet radiation and cigarette smoke. To deal with these threats, five major DNA repair pathways, which are principally defined by the type of lesions they repair, have evolved. Defects in these repair pathways predispose individuals to a wide variety of cancers, and at the same time can be therapeutically exploited to target tumours with defective DNA repair.Dysregulation of these repair pathways are also frequently observed in cancer, presenting both opportunities and challenges for cancer therapy: downregulated repair pathways sensitise tumours to DNA-damaging therapies, while upregulated repair pathways cause resistance to these therapies.The primary aim of this thesis is to obtain a comprehensive and in-depth understanding of the mechanisms and roles of these major DNA repair pathways in the context of breast cancer. This will be beneficial for predicting response to radiation and chemotherapy, and for developing novel targeted therapies in this common type of malignancy.By careful literature search and consulting a domain expert, the research presented in this thesis started with a manual curation of six DNA repair pathways, including the five major repair pathways and the Fanconi anaemia pathway that is closely associated with breast cancer susceptibility. Six comprehensive pathway figures were generated, each for one repair pathway, describing in total 195 genes and 138 reactions with direct relevance to DNA repair. Moreover, to facilitate a deep understanding of the repair mechanisms, a detailed description for each reaction was given, importantly including the literature references used for curating the reaction. This curation work enables a mechanistic understanding of how cells respond to DNA damage, and provides a solid foundation for the subsequent computational analyses.In the second study of this PhD research, I performed a personalised pathway analysis to investigate the status of homologous recombination (HR) pathway dysregulation in individual sporadic breast tumours, its association with HR repair deficiency and its impact on tumour characteristics.Specifically, using the expression values of the HR genes curated in the previous study, I calculated an HR score for each tumour that quantifies the extent of HR pathway dysregulation in that tumour.Based on that score, I observed a great diversity in HR dysregulation between and within gene expression-based breast cancer subtypes. And by comparing to two published HR-defect signatures, I found HR pathway dysregulation reflects HR repair deficiency. Furthermore, I uncovered a novel association between HR pathway dysregulation and chromosomal instability (CIN): tumours with more-dysregulated HR tend to have higher CIN. Although CIN has long been considered to be a iii hallmark of most solid tumours, with recent studies highlighting its importance in tumour evolution and drug resistance, the molecular basis of CIN in spora...

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Molecular Genetics of Fanconi Anaemia

Green

Kupfer

2012

Encyclopedia of Life Sciences

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Cells derived from Fanconi anaemia (FA) patients display hypersensitivity to deoxyribonucleic acid (DNA) cross‐linking agents such as MMC and DEB. Treatment with these agents induces an abnormally prolonged cell cycle arrest in S phase and an accumulation of cells with 4N DNA. Based on this response, the FA pathway has been hypothesised to function in sensing DNA damage induced by these agents and in initiating its repair. This hypothesis has been supported by work elucidating the interactions of FA proteins with proteins known to be involved in DNA‐damage sensing, signalling and repair. Additionally, a significant body of work has pointed to a role of the FA pathway in the cellular response to oxidative stress. Although the exact mechanisms and functions of the FA pathway are yet to be discovered, the interaction of the members of the FA pathway with proteins associated with DNA repair, cellular signalling and oxidative stress management leads to the hypothesis that the FA pathway proteins serve many varied functions throughout the cell. Key Concepts: The FA pathway overlaps significantly with other DNA repair pathways such as homologous recombination, translesion synthesis and mismatch repair. FA pathway proteins are involved in the intricate cellular signalling that occurs following DNA damage. FA pathway proteins are involved in regulating oxidative stress. FA mutant cells display hypersensitivity to DNA damage, particularly DNA crosslink's. FA patients are particularly prone to malignancy, especially myeloid leukemia and squamous cell carcinomas of the head and neck and genitourinary track.

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The Fanconi anaemia pathway orchestrates incisions at sites of crosslinked DNA

Cited by 99 publications

References 151 publications

Heightened DNA damage response impairs hematopoiesis in Fanconi anemia

Heightened DNA damage response impairs hematopoiesis in Fanconi anemia

Computational analysis of DNA repair pathways in breast cancer

Molecular Genetics of Fanconi Anaemia

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