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1.
Mol Cell ; 78(5): 951-959.e6, 2020 06 04.
Artículo en Inglés | MEDLINE | ID: mdl-32359443

RESUMEN

BRCA1 promotes the DNA end resection and RAD51 loading steps of homologous recombination (HR). Whether these functions can be uncoupled, and whether mutant proteins retaining partial activity can complement one another, is unclear and could affect the severity of BRCA1-associated Fanconi anemia (FA). Here we generated a Brca1CC mouse with a coiled-coil (CC) domain deletion. Brca1CC/CC mice are born at low frequencies, and post-natal mice have FA-like abnormalities, including bone marrow failure. Intercrossing with Brca1Δ11, which is homozygous lethal, generated Brca1CC/Δ11 mice at Mendelian frequencies that were indistinguishable from Brca1+/+ mice. Brca1CC and Brca1Δ11 proteins were individually responsible for counteracting 53BP1-RIF1-Shieldin activity and promoting RAD51 loading, respectively. Thus, Brca1CC and Brca1Δ11 alleles represent separation-of-function mutations that combine to provide a level of HR sufficient for normal development and hematopoiesis. Because BRCA1 activities can be genetically separated, compound heterozygosity for functional complementary mutations may protect individuals from FA.


Asunto(s)
Proteína BRCA1/genética , Recombinación Homóloga/genética , Proteína 1 de Unión al Supresor Tumoral P53/genética , Animales , Proteína BRCA1/metabolismo , Roturas del ADN de Doble Cadena , Reparación del ADN , Exones , Anemia de Fanconi/genética , Anemia de Fanconi/metabolismo , Femenino , Células HEK293 , Humanos , Masculino , Ratones , Ratones Endogámicos C3H , Ratones Endogámicos C57BL , Ratones Noqueados , Mutación , Recombinasa Rad51/genética , Recombinasa Rad51/metabolismo , Proteína 1 de Unión al Supresor Tumoral P53/metabolismo
2.
J Sports Sci ; 42(9): 825-839, 2024 May.
Artículo en Inglés | MEDLINE | ID: mdl-38896557

RESUMEN

Hormonal contraceptive (HC) users have a different ovarian hormonal profile compared to eumenorrheic women. Due to the prevalence of HC use amongst sportswomen, there has been increased research efforts to understand their impact on exercise performance. The aim was to audit this research. Studies identified were assessed for HC type, athlete calibre, performance outcome, study design, and quality of methodological control regarding ovarian hormonal profiles. Sixty-eight different HCs were reported across 61 studies. Monophasic combined oral contraceptive (OCP) pills represented 60% of HCs, followed by other pills [34%, phasic-combined, progestogen-only, and un-specified], phasic and long acting reversible contraceptives [5%, vaginal ring, patch, implant, injection, intrauterine system] and unspecified HCs (1%). Eleven percent of participants using HCs were classified as highly trained or elite/international with no participants being classed as world class. Whilst the number of studies involving HCs has increased two-fold over the past decade, the number of studies ranked as gold standard has not increased (HC; 2003-57%, 2011-55%, 2022-43%. OCP; 2003-14%, 2011-17%, 2022-12%). Future research assessing HCs and exercise performance should adopt high-quality research designs and include a broader range of HCs in highly trained to world-class populations to increase the reach and impact of research in this area.


Asunto(s)
Rendimiento Atlético , Humanos , Femenino , Rendimiento Atlético/fisiología , Ejercicio Físico/fisiología , Agentes Anticonceptivos Hormonales/administración & dosificación , Anticonceptivos Hormonales Orales/administración & dosificación , Proyectos de Investigación
3.
Cancer Res ; 80(13): 2848-2860, 2020 07 01.
Artículo en Inglés | MEDLINE | ID: mdl-32213544

RESUMEN

BRCA1 gene mutations impair homologous recombination (HR) DNA repair, resulting in cellular senescence and embryonic lethality in mice. Therefore, BRCA1-deficient cancers require adaptations that prevent excessive genomic alterations from triggering cell death. RNF168-mediated ubiquitination of γH2AX at K13/15 (ub-H2AX) serves as a recruitment module for the localization of 53BP1 to DNA break sites. Here, we found multiple BRCA1-mutant cancer cell lines and primary tumors with low levels of RNF168 protein expression. Overexpression of ectopic RNF168 or a ub-H2AX fusion protein induced cell death and delayed BRCA1-mutant tumor formation. Cell death resulted from the recruitment of 53BP1 to DNA break sites and inhibition of DNA end resection. Strikingly, reintroduction of BRCA1 or 53BP1 depletion restored HR and rescued the ability of cells to maintain RNF168 and ub-H2AX overexpression. Thus, downregulation of RNF168 protein expression is a mechanism for providing BRCA1-null cancer cell lines with a residual level of HR that is essential for viability. Overall, our work identifies loss of RNF168 ubiquitin signaling as a proteomic alteration that supports BRCA1-mutant carcinogenesis. We propose that restoring RNF168-ub-H2AX signaling, potentially through inhibition of deubiquitinases, could represent a new therapeutic approach. SIGNIFICANCE: This study explores the concept that homologous recombination DNA repair is not an all-or-nothing concept, but a spectrum, and that where a tumor stands on this spectrum may have therapeutic relevance.See related commentary by Wang and Wulf, p. 2720.


Asunto(s)
Neoplasias , Ubiquitina , Animales , Proteína BRCA1/genética , Daño del ADN , Ratones , Neoplasias/genética , Proteómica , Ubiquitina/metabolismo , Ubiquitina-Proteína Ligasas/genética , Ubiquitina-Proteína Ligasas/metabolismo , Ubiquitinación
4.
Cell Rep ; 24(13): 3513-3527.e7, 2018 09 25.
Artículo en Inglés | MEDLINE | ID: mdl-30257212

RESUMEN

BRCA1 functions in homologous recombination (HR) both up- and downstream of DNA end resection. However, in cells with 53BP1 gene knockout (KO), BRCA1 is dispensable for the initiation of resection, but whether BRCA1 activity is entirely redundant after end resection is unclear. Here, we found that 53bp1 KO rescued the embryonic viability of a Brca1ΔC/ΔC mouse model that harbors a stop codon in the coiled-coil domain. However, Brca1ΔC/ΔC;53bp1-/- mice were susceptible to tumor formation, lacked Rad51 foci, and were sensitive to PARP inhibitor (PARPi) treatment, indicative of suboptimal HR. Furthermore, BRCA1 mutant cancer cell lines were dependent on truncated BRCA1 proteins that retained the ability to interact with PALB2 for 53BP1 KO induced RAD51 foci and PARPi resistance. Our data suggest that the overall efficiency of 53BP1 loss of function induced HR may be BRCA1 mutation dependent. In the setting of 53BP1 KO, hypomorphic BRCA1 proteins are active downstream of end resection, promoting RAD51 loading and PARPi resistance.


Asunto(s)
Proteína BRCA1/genética , Resistencia a Antineoplásicos , Recombinación Homóloga , Neoplasias Mamarias Experimentales/genética , Inhibidores de Poli(ADP-Ribosa) Polimerasas/uso terapéutico , Proteína 1 de Unión al Supresor Tumoral P53/genética , Animales , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Proteína BRCA1/metabolismo , Proteína del Grupo de Complementación N de la Anemia de Fanconi/metabolismo , Femenino , Células HEK293 , Humanos , Mutación con Pérdida de Función , Células MCF-7 , Neoplasias Mamarias Experimentales/tratamiento farmacológico , Ratones , Inhibidores de Poli(ADP-Ribosa) Polimerasas/farmacología , Recombinasa Rad51/metabolismo , Proteína 1 de Unión al Supresor Tumoral P53/metabolismo
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