RESUMO
TAp63, but not its homolog p53, eliminates oocytes that suffered DNA damage. An equivalent gene for guarding the male germ line is currently not known. Here we identify hitherto unknown human p63 transcripts with unique 5'-ends derived from incorporated exons upstream of the currently mapped TP63 gene. These unique p63 transcripts are highly and specifically expressed in testis. Their most upstream region corresponds to a LTR of the human endogenous retrovirus 9 (ERV9). The insertion of this LTR upstream of the TP63 locus occurred only recently in evolution and is unique to humans and great apes (Hominidae). A corresponding p63 protein is the sole p63 species in healthy human testis, and is strongly expressed in spermatogenic precursors but not in mature spermatozoa. In response to DNA damage, this human male germ-cell-encoded TAp63 protein (designated GTAp63) is activated by caspase cleavage near its carboxyterminal domain and induces apoptosis. Human testicular cancer tissues and cell lines largely lost p63 expression. However, pharmacological inhibition of histone deacetylases completely restores p63 expression in testicular cancer cells (>3,000-fold increase). Our data support a model whereby testis-specific GTAp63 protects the genomic integrity of the male germ line and acts as a tumor suppressor. In Hominidae, this guardian function was greatly enhanced by integration of an endogenous retrovirus upstream of the TP63 locus that occurred 15 million years ago. By providing increased germ-line stability, this event may have contributed to the evolution of hominids and enabled their long reproductive periods.
Assuntos
Apoptose , Retrovirus Endógenos/metabolismo , Hominidae/metabolismo , Espermatozoides/metabolismo , Transativadores/metabolismo , Proteínas Supressoras de Tumor/metabolismo , Sequência de Aminoácidos , Animais , Apoptose/efeitos dos fármacos , Apoptose/genética , Dano ao DNA , Retrovirus Endógenos/efeitos dos fármacos , Éxons/genética , Regulação da Expressão Gênica/efeitos dos fármacos , Inativação Gênica/efeitos dos fármacos , Inibidores de Histona Desacetilases/farmacologia , Humanos , Masculino , Dados de Sequência Molecular , Mutagênese Insercional/genética , Especificidade de Órgãos/efeitos dos fármacos , Isoformas de Proteínas/química , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , Espermatozoides/efeitos dos fármacos , Espermatozoides/patologia , Sequências Repetidas Terminais/genética , Neoplasias Testiculares/enzimologia , Neoplasias Testiculares/patologia , Testículo/efeitos dos fármacos , Testículo/metabolismo , Testículo/patologia , Transativadores/química , Transativadores/genética , Fatores de Transcrição , Transcrição Gênica , Proteínas Supressoras de Tumor/química , Proteínas Supressoras de Tumor/genéticaRESUMO
We present a historical overview of forest concepts and definitions, linking these changes with distinct perspectives and management objectives. Policies dealing with a broad range of forest issues are often based on definitions created for the purpose of assessing global forest stocks, which do not distinguish between natural and planted forests or reforests, and which have not proved useful in assessing national and global rates of forest regrowth and restoration. Implementing and monitoring forest and landscape restoration requires additional approaches to defining and assessing forests that reveal the qualities and trajectories of forest patches in a spatially and temporally dynamic landscape matrix. New technologies and participatory assessment of forest states and trajectories offer the potential to operationalize such definitions. Purpose-built and contextualized definitions are needed to support policies that successfully protect, sustain, and regrow forests at national and global scales. We provide a framework to illustrate how different management objectives drive the relative importance of different aspects of forest state, dynamics, and landscape context.