RESUMEN
Increased levels and non-telomeric roles have been reported for shelterin proteins, including RAP1 in cancers. Herein using Rap1 null mice, we provide the genetic evidence that mammalian Rap1 plays a major role in hematopoietic stem cell survival, oncogenesis and response to chemotherapy. Strikingly, this function of RAP1 is independent of its association with the telomere or with its known partner TRF2. We show that RAP1 interacts with many members of the DNA damage response (DDR) pathway. RAP1 depleted cells show reduced interaction between XRCC4/DNA Ligase IV and DNA-PK, and are impaired in DNA Ligase IV recruitment to damaged chromatin for efficient repair. Consistent with its role in DNA damage repair, RAP1 loss decreases double-strand break repair via NHEJ in vivo, and consequently reduces B cell class switch recombination. Finally, we discover that RAP1 levels are predictive of the success of chemotherapy in breast and colon cancer.
Asunto(s)
Antineoplásicos/farmacología , Carcinogénesis/metabolismo , Células Madre Hematopoyéticas/citología , Células Madre Hematopoyéticas/metabolismo , Proteínas de Unión a Telómeros/metabolismo , Proteínas de Unión al GTP rap1/metabolismo , Animales , Carcinogénesis/efectos de los fármacos , Carcinogénesis/patología , Línea Celular , Supervivencia Celular/efectos de los fármacos , Supervivencia Celular/efectos de la radiación , Daño del ADN , ADN Ligasa (ATP)/metabolismo , Reparación del ADN/efectos de los fármacos , Reparación del ADN/efectos de la radiación , Proteína Quinasa Activada por ADN/metabolismo , Fluorouracilo/farmacología , Rayos gamma , Inestabilidad Genómica/efectos de los fármacos , Inestabilidad Genómica/efectos de la radiación , Células Madre Hematopoyéticas/efectos de los fármacos , Células Madre Hematopoyéticas/efectos de la radiación , Humanos , Ratones Noqueados , Mutágenos/toxicidad , Unión Proteica/efectos de los fármacos , Unión Proteica/efectos de la radiación , Proteínas Proto-Oncogénicas c-myc/metabolismo , Complejo Shelterina , Análisis de SupervivenciaRESUMEN
Inflammatory signaling underlies many diseases, from arthritis to cancer. Our understanding of inflammation has thus far been limited to the world of proteins, because we are only just beginning to understand the role that noncoding RNAs (ncRNA) might play. It is now clear that ncRNA do not constitute transcriptional 'noise' but instead harbor physiological functions in controlling signaling pathways. In this review, we cover the newly discovered mechanisms and functions of ncRNAs in the regulation of inflammatory signaling. We also describe advances in experimental techniques allowing this field of research to take root. These findings have opened new avenues for putative therapeutic intervention in inflammatory diseases, which may be seen translated into clinical outcomes in the future.