Upregulation of Fanconi Anemia DNA Repair Genes in Melanoma Compared with Non-Melanoma Skin Cancer

Kao, Wynn H.; Riker, Adam I.; Kushwaha, Deepa; Ng, Kimberly; Enkemann, Steven A.; Jove, Richard; Buettner, Ralf; Zinn, Pascal O.; Sánchez, Néstor P.; Villa, Jaime; D’Andrea, Alan D.; Sánchez, Jorge; Kennedy, Richard D.; Chen, Clark C.; Matta, Jaime

doi:10.1038/jid.2011.181

Cited by 24 publications

(21 citation statements)

References 13 publications

(16 reference statements)

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“…Similarly, FANC proteins including FANCM were found to be transcriptionally upregulated in melanomas [12]. Furthermore, the FANC pathway was implicated in resistance to chemotherapeutic agents [13], [14].…”

Section: Discussionmentioning

confidence: 99%

The Mph1 Helicase Can Promote Telomere Uncapping and Premature Senescence in Budding Yeast

Luke-Glaser

Luke

2012

PLoS ONE

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Double strand breaks (DSBs) can be repaired via either Non-Homologous End Joining (NHEJ) or Homology directed Repair (HR). Telomeres, which resemble DSBs, are refractory to repair events in order to prevent chromosome end fusions and genomic instability. In some rare instances telomeres engage in Break-Induced Replication (BIR), a type of HR, in order to maintain telomere length in the absence of the enzyme telomerase. Here we have investigated how the yeast helicase, Mph1, affects DNA repair at both DSBs and telomeres. We have found that overexpressed Mph1 strongly inhibits BIR at internal DSBs however allows it to proceed at telomeres. Furthermore, while overexpressed Mph1 potently inhibits NHEJ at telomeres it has no effect on NHEJ at DSBs within the chromosome. At telomeres Mph1 is able to promote telomere uncapping and the accumulation of ssDNA, which results in premature senescence in the absence of telomerase. We propose that Mph1 is able to direct repair towards HR (thereby inhibiting NHEJ) at telomeres by remodeling them into a nuclease-sensitive structure, which promotes the accumulation of a recombinogenic ssDNA intermediate. We thus put forward that Mph1 is a double-edge sword at the telomere, it prevents NHEJ, but promotes senescence in cells with dysfunctional telomeres by increasing the levels of ssDNA.

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Section: Discussionmentioning

confidence: 99%

The Mph1 Helicase Can Promote Telomere Uncapping and Premature Senescence in Budding Yeast

Luke-Glaser

Luke

2012

PLoS ONE

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“…Our results suggest that the overexpression of FANCM may give rise to chemo-resistant cells and suggest that combinatorial therapies utilizing ICL-inducing agents in conjunction with FANCM inhibitors would improve the efficacy of tumor treatment. Our results specifically address the consequences of Mph1 OE, but the up-regulation of other Fanconi genes is also associated with melanoma (88) and cellular resistance to DNA damaging agents (89,90). Thus, these therapeutic implications may also extend to other Fanconi proteins and their inhibitors.…”

Section: Discussionmentioning

confidence: 99%

Rad5-dependent DNA Repair Functions of the Saccharomyces cerevisiae FANCM Protein Homolog Mph1

Daee

Ferrari

Longerich

et al. 2012

Journal of Biological Chemistry

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Background: Yeast proteins homologous to human Fanconi proteins exist, but their cross-link repair functions are undefined. Results: Mutants are cross-link-sensitive, and Mph1 overexpression protects yeast cells. Conclusion:The yeast pathway is epistatic with rad5 and rad51, and the Mph1 helicase stabilizes ICL-stalled replication forks in a Rad5-dependent manner. Significance: Rad5 directs the yeast Fanconi-like interstrand cross-link repair pathway.

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“…Higher expression of FANC genes has been detected in melanoma (12) and is related to resistance to chemotherapy in other pathologies. In multiple myelomas, FANCF overexpression associates with melphalan resistance (13).…”

Section: Discussionmentioning

confidence: 99%

“…Mutation of these genes at the germinal line results in a syndrome characterized by progressive bone marrow depletion caused by apoptosis of the hematopoietic progenitors, congenital malformations, and high predisposition to malignancies, known as FA (11). On the contrary, overexpression of some of the FANC genes has been associated with melanoma (12) and the resistance to chemotherapy in multiple myeloma (13), ovarian cancer (14), and glioma (15).…”

mentioning

confidence: 99%

Elevated FANCA expression determines a worse prognosis in chronic lymphocytic leukemia and interferes with p53 function

et al. 2019

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Chronic lymphocytic leukemia (CLL) is characterized by a failure in the mechanisms of apoptosis that leads to an accumulation of mature B cells in peripheral blood, bone marrow, and lymphoid organs. The molecular basis of CLL remains unknown. Certain cytogenetic and molecular markers determine a bad prognosis in CLL. Fanconi anemia complementation (FANC) proteins have been related to chromosomal instability and alterations in the mechanisms of p53 activation, control of cell cycle, and apoptosis. We investigated the role of certain FANC proteins in CLL. Our data identified a group of patients with CLL with high expression of FANCA in peripheral B‐CLL cells and we established its relationship with the deletion of 11q23 and a worse prognosis. When we investigated the molecular mechanisms of this bad prognosis, we observed a reduction in the expression of 2 p53 target genes, p21 and ΔNp73, in CLL primary cells transfected with FANCA. Functional studies demonstrated an impairment of p53 by FANCA. Moreover, we obtained evidence of a cooperation between FANCA and the NEDD8–interacting protein NUB1L in the destabilization of p53. For the first time, FANCA is reported as a bad prognosis marker by a mechanism other than its role in the Fanconi anemia–breast cancer DNA repair pathway.—Bravo‐Navas, S., Yáñez, L., Romón, Í., Pipaón, C. Elevated FANCA expression determines a worse prognosis in chronic lymphocytic leukemia and interferes with p53 function. FASEB J. 33,10477–10489 (2019). http://www.fasebj.org

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Upregulation of Fanconi Anemia DNA Repair Genes in Melanoma Compared with Non-Melanoma Skin Cancer

Cited by 24 publications

References 13 publications

The Mph1 Helicase Can Promote Telomere Uncapping and Premature Senescence in Budding Yeast

The Mph1 Helicase Can Promote Telomere Uncapping and Premature Senescence in Budding Yeast

Rad5-dependent DNA Repair Functions of the Saccharomyces cerevisiae FANCM Protein Homolog Mph1

Elevated FANCA expression determines a worse prognosis in chronic lymphocytic leukemia and interferes with p53 function

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