The Fanconi anemia group A protein modulates homologous repair of DNA double-strand breaks in mammalian cells

Yang, Yun‐Gui; Herceg, Zdenko; Nakanishi, Koji; Demuth, Ilja; Piccoli, C.; Michelon, Jocelyne; Hildebrand, Gabriele; Jasin, Maria; Digweed, Martin; Wang, Zhaoqi

doi:10.1093/carcin/bgi134

Cited by 73 publications

(81 citation statements)

References 39 publications

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“…We validated the elevated expression of Rad51, Brca1, Brip1 and Mre11a in p-9 HZp53-MSCs (Figure 6g). Fanconi Anemia proteins (Fanci, Fanca, Fancb and Fancd2) that execute cross-linked DNA repair, known to engage HR, 34 also appeared in the upregulated cluster (Figure 6f) as well as Xrcc5 (Ku80) and Mre11a, known to have a role in non-homologous end joining (NHEJ; Figure 6f). Figure 6f illustrates a 'heat map' of expression levels of all the upregulated genes involved in HRDRP and additional DNA repair pathways, suggesting that HRDRP is one of the major mechanisms leading to LOH.…”

Section: Resultsmentioning

confidence: 99%

The onset of p53 loss of heterozygosity is differentially induced in various stem cell types and may involve the loss of either allele

et al. 2014

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1,5 p53 loss of heterozygosity (p53LOH) is frequently observed in Li-Fraumeni syndrome (LFS) patients who carry a mutant (Mut) p53 germ-line mutation. Here, we focused on elucidating the link between p53LOH and tumor development in stem cells (SCs). Although adult mesenchymal stem cells (MSCs) robustly underwent p53LOH, p53LOH in induced embryonic pluripotent stem cells (iPSCs) was significantly attenuated. Only SCs that underwent p53LOH induced malignant tumors in mice. These results may explain why LFS patients develop normally, yet acquire tumors in adulthood. Surprisingly, an analysis of single-cell sub-clones of iPSCs, MSCs and ex vivo bone marrow (BM) progenitors revealed that p53LOH is a bi-directional process, which may result in either the loss of wild-type (WT) or Mut p53 allele. Interestingly, most BM progenitors underwent Mutp53LOH. Our results suggest that the bi-directional p53LOH process may function as a cell-fate checkpoint. The loss of Mutp53 may be regarded as a DNA repair event leading to genome stability. Indeed, gene expression analysis of the p53LOH process revealed upregulation of a specific chromatin remodeler and a burst of DNA repair genes. However, in the case of loss of WTp53, cells are endowed with uncontrolled growth that promotes cancer.

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Section: Resultsmentioning

confidence: 99%

The onset of p53 loss of heterozygosity is differentially induced in various stem cell types and may involve the loss of either allele

et al. 2014

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“…FANCA was also found to be involved in psoralen ICL-induced mutagenesis and in spontaneous and UV light-induced base substitution mutagenesis in human cells, implying its involvement in the mutagenic translesion synthesis of DNA damage (28,29). Additionally, FANCA was shown to be required for recruiting FANCO/RAD51 and FANCD1/BRCA2 into mitomycin C-induced nuclear foci, indicating its role in the homologous recombination repair of ICLs (12,30,31). These data imply that FANCA may play multiple roles in DNA metabolism and transactions.…”

Section: Fanconi Anemia (Fa)mentioning

confidence: 99%

Fanconi Anemia Complementation Group A (FANCA) Protein Has Intrinsic Affinity for Nucleic Acids with Preference for Single-stranded Forms

Yuan

Qian

Zhao

et al. 2012

Journal of Biological Chemistry

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Background:The FANCA (Fanconi anemia complementation group A) gene is mutated in ϳ60% of Fanconi anemia patients, but no biochemical activity has been identified. Results: Purified FANCA binds to nucleic acids of a certain length through its C terminus. Conclusion: FANCA has an intrinsic affinity for nucleic acids with a strong preference for single-stranded forms. Significance: Unveiling the biochemical activity of FANCA is critical for understanding its functions in DNA repair.

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“…Interestingly, recent evidence suggests that DNA cross-links may be preferentially repaired by the singlestrand annealing subset of HR (Jonnalagadda et al 2005). Cold Spring Harbor Laboratory Press on May 12, 2018 -Published by genesdev.cshlp.org Downloaded from Murine cells deficient in components of complex 1 or FANCD2 demonstrate abnormal single-strand annealing following cross-linker damage, suggesting a specific role for the FA pathway in this subset of HR Yang et al 2005).…”

Section: Recruitment Of Dna Repair Proteinsmentioning

confidence: 99%

The Fanconi Anemia/BRCA pathway: new faces in the crowd

Kennedy¹,

D’Andrea²

2005

Genes Dev.

359

345

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Over the past few years, study of the rare inherited chromosome instability disorder, Fanconi Anemia (FA), has uncovered a novel DNA damage response pathway. Through the cooperation of multiple proteins, this pathway regulates a complicated cellular response to DNA cross-linking agents and other genotoxic stresses. In this article we review recent data identifying new components of the FA pathway that implicate it in several aspects of the DNA damage response, including the direct processing of DNA, translesion synthesis, homologous recombination, and cell cycle regulation. We also discuss new findings that explain how the FA pathway is regulated through the processes of ubiquitination and deubiquitination. We then consider the clinical implications of our current understanding of the FA pathway, particularly in the development and treatment of malignancy in heterozygous carriers of FA mutations or in patients with sporadic cancers. We consider how recent studies of p53-mediated apoptosis and loss of p53 function in models of FA may help explain the clinical features of the disease and finally present a hypothesis to account for the specificity of the FA pathway in the response to DNA cross-links.

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The Fanconi anemia group A protein modulates homologous repair of DNA double-strand breaks in mammalian cells

Cited by 73 publications

References 39 publications

The onset of p53 loss of heterozygosity is differentially induced in various stem cell types and may involve the loss of either allele

The onset of p53 loss of heterozygosity is differentially induced in various stem cell types and may involve the loss of either allele

Fanconi Anemia Complementation Group A (FANCA) Protein Has Intrinsic Affinity for Nucleic Acids with Preference for Single-stranded Forms

The Fanconi Anemia/BRCA pathway: new faces in the crowd

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