Artículo
FANCD2 maintains replication fork stability during misincorporation of the DNA demethylation products 5-hydroxymethyl-2’-deoxycytidine and 5-hydroxymethyl-2’-deoxyuridine
Autor/es | Peña Gómez, Mª José
Moreno Gordillo, Paula Narmonté, Milda García Calderón, Clara Beatriz Ruksenaité, Audronė Klimašauskas, Saulius Valle Rosado, Iván |
Departamento | Universidad de Sevilla. Departamento de Genética |
Fecha de publicación | 2022 |
Fecha de depósito | 2022-11-07 |
Publicado en |
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Resumen | Fanconi anemia (FA) is a rare hereditary disorder caused by mutations in any one of the FANC genes. FA cells are mainly characterized by extreme hypersensitivity to interstrand crosslink (ICL) agents. Additionally, the FA ... Fanconi anemia (FA) is a rare hereditary disorder caused by mutations in any one of the FANC genes. FA cells are mainly characterized by extreme hypersensitivity to interstrand crosslink (ICL) agents. Additionally, the FA proteins play a crucial role in concert with homologous recombination (HR) factors to protect stalled replication forks. Here, we report that the 5-methyl-2’-deoxycytidine (5mdC) demethylation (pathway) intermediate 5-hydroxymethyl-2’-deoxycytidine (5hmdC) and its deamination product 5-hydroxymethyl-2’-deoxyuridine (5hmdU) elicit a DNA damage response, chromosome aberrations, replication fork impairment and cell viability loss in the absence of FANCD2. Interestingly, replication fork instability by 5hmdC or 5hmdU was associated to the presence of Poly(ADP-ribose) polymerase 1 (PARP1) on chromatin, being both phenotypes exacerbated by olaparib treatment. Remarkably, Parp1−/− cells did not show any replication fork defects or sensitivity to 5hmdC or 5hmdU, suggesting that retained PARP1 at base excision repair (BER) intermediates accounts for the observed replication fork defects upon 5hmdC or 5hmdU incorporation in the absence of FANCD2. We therefore conclude that 5hmdC is deaminated in vivo to 5hmdU, whose fixation by PARP1 during BER, hinders replication fork progression and contributes to genomic instability in FA cells. |
Agencias financiadoras | Ministerio de Ciencia e Innovación (MICIN). España Junta de Andalucía Universidad de Sevilla Gobierno de España Consejo Europeo de Investigación |
Identificador del proyecto | 8.06.03.3073 (RTI2018-100692-B-100)
PI-0005-2018 18.06.03.2404 (P18-RT-1271) 18.06.03.2319 (US-1381081) RYC2015-18670 742654 |
Cita | Peña Gómez, M.J., Moreno Gordillo, P., Narmonté, M., García Calderón, C.B., Ruksenaité, A., Klimašauskas, S. y Valle Rosado, I. (2022). FANCD2 maintains replication fork stability during misincorporation of the DNA demethylation products 5-hydroxymethyl-2’-deoxycytidine and 5-hydroxymethyl-2’-deoxyuridine. Cell Death and Disease, 13 (5), 503. https://doi.org/10.1038/s41419-022-04952-0. |
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FANCD2 maintains replication.pdf | 3.319Mb | [PDF] | Ver/ | |