Regulation of senescence by microRNA biogenesis factors

Abstract

Senescence represents a state of indefinite growth arrest in cells that have reached the end of their replicative life span, have become damaged, or express aberrant levels of cancer-related proteins. While senescence is widely considered to represent a tumor-suppressive mechanism, the accumulation of senescent cells in tissues of older organisms is believed to underlie age-associated losses in physiologic function and age-related diseases. With the emergence of microRNAs (miRNAs) as a major class of molecular regulators of senescence, we review the transcriptional and post-transcriptional factors that control senescence-associated microRNA biosynthesis. Focusing on their enhancement or repression of senescence, we describe the transcription factors that govern the synthesis of primary (pri-)miRNAs, the proteins that control the nuclear processing of pri-miRNAs into precursor (pre-)miRNAs, including RNA editing enzymes, RNases, and RNA helicases, and the cytoplasmic proteins that affect the final processing of pre-miRNAs into mature miRNAs. We discuss how miRNA biogenesis proteins promote or inhibit senescence, and thus influence the senescent phenotype that affects normal tissue function and pathology.

Figure 1

Schematic representation of microRNA biogenesis, depicting the senescence-associated factors involved. Top, transcriptional regulators of senescence-associated primary (pri)-miRNA biosynthesis (rectangles). Middle, regulators of pri-miRNA processing into pre-mRNAs, including components of the microprocessor complex (Drosha, DGCR8 and accessory factors, ovals). Bottom, regulators of pre-miRNA processing into mature miRNAs, particularly the components of the RISC and accessory proteins (ovals). On the right part of the schematic (blue background) are factors that mainly promote senescence, either by increasing the expression of growth-inhibitory, senescence-enhancing microRNAs (e.g., miR-34a or let-7, blue text) or by inhibiting the production of proliferative, growth-promoting, oncogenic miRNA (e.g., miR-221/miR-222, red text). On the left part of the schematic (red background) are factors that mainly repress senescence, either by promoting the expression of proliferative, oncogenic miRNAs (e.g., miR-21, the miR-17-92 cluster, red text) or by lowering the production of senescence-promoting miRNAs (e.g., miR-34a, let-7, miR-1, blue text).